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Exercise-induced cardioprotection against myocardial ischemia-reperfusion injury
Abstract
Myocardial ischemia-reperfusion (IR) injury is a major contributor to the morbidity and mortality associated with coronary artery disease. Muscular exercise is a countermeasure to protect against IR-induced cardiac injury in both young and old animals. Specifically, regular bouts of endurance exercise protect the heart against all levels of IR-induced injury. Proposed mechanisms to explain the cardioprotective effects of exercise include alterations in coronary circulation, expression of endoplasmic reticulum stress proteins, increased cyclooxygenase-2 activity, induction of myocardial heat shock proteins, improved cardiac antioxidant capacity, and/or elevation of ATP-sensitive potassium channels on both the sarcolemmal and the mitochondrial inner membranes. Moreover, it seems possible that other, yet to be defined, mechanisms of exercise-induced cardioprotection may also exist. Of the known putative cardioprotective mechanisms, current evidence suggests that elevated myocardial levels of antioxidants and increased expression of sarcolemmal ATP-sensitive potassium channels are both contributors to exercise-induced cardioprotection against IR injury. At present, it is unclear if these two protective mediators act independently or interact to contribute to exercise-induced cardioprotection. Understanding the molecular basis for exercise-induced cardioprotection will provide the required knowledge base to develop therapeutic approaches to protect the heart during an IR insult.
... Continuing research is aimed to explore the therapeutic interventions against IR injury. Although numerous pharmacological and preconditioning approaches to cardioprotection have been explored, regular exercise participation is recognized as an important, cost-effective, and safer lifestyle intervention in the prevention and treatment of IR injury (10)(11)(12)(13)(14). Redundant protective effects are evident in the exercised heart, namely, increased levels of heat shock proteins (15), altered nitric oxide (NO) signaling (16)(17)(18), enhanced Ca 2+ handling proteins (19), improved ATP-sensitive potassium channels (20), and enhanced endogenous antioxidant (13,21). ...
... Continuing research is aimed to explore the therapeutic interventions against IR injury. Although numerous pharmacological and preconditioning approaches to cardioprotection have been explored, regular exercise participation is recognized as an important, cost-effective, and safer lifestyle intervention in the prevention and treatment of IR injury (10)(11)(12)(13)(14). Redundant protective effects are evident in the exercised heart, namely, increased levels of heat shock proteins (15), altered nitric oxide (NO) signaling (16)(17)(18), enhanced Ca 2+ handling proteins (19), improved ATP-sensitive potassium channels (20), and enhanced endogenous antioxidant (13,21). ...
... The proposed mechanisms underlying exercise-induced cardioprotection in IR are numerous. Some are systemic (12), some are vascular (12)(13)(14)21), some are neural (38,39), some are structural (9), and some are energetic/metabolic (40,41) including expression of selected mitochondrial proteins resulting in a mitochondrial phenotype that is resistant to IR-induced injury (13,19). While these studies generally support exerciseinduced adaptations that produce resistance to injury, few address the mitochondrial functional consequences following an injury. ...
Rationale: Regular active exercise is considered therapeutic for cardiovascular disease, in part by increasing mitochondrial respiratory capacity, but a significant amount of exercise capacity is determined genetically. Animal models, demonstrating either high capacity aerobic running (HCR) or low capacity aerobic running (LCR) phenotypes, have been developed to study the intrinsic contribution, with HCR rats subsequently characterized as “disease resistant” and the LCRs as “disease prone.” Enhanced cardioprotection in HCRs has been variable and mutifactoral, but likely includes a metabolic component. These studies were conducted to determine the influence of intrinsic aerobic phenotype on cardiac mitochondrial function before and after ischemia and reperfusion.
Methods: A total of 34 HCR and LCR rats were obtained from the parent colony at the University of Toledo, housed under sedentary conditions, and fed normal chow. LCR and HCR animals were randomly assigned to either control or ischemia-reperfusion (IR). On each study day, one HCR/LCR pair was anesthetized, and hearts were rapidly excised. In IR animals, the hearts were immediately flushed with iced hyperkalemic, hyperosmotic, cardioplegia solution, and subjected to global hypothermic ischemic arrest (80 min). Following the arrest, the hearts underwent warm reperfusion (120 min) using a Langendorff perfusion system. Following reperfusion, the heart was weighed and the left ventricle (LV) was isolated. A midventricular ring was obtained to estimate infarction size [triphenyltetrazolium chloride (TTC)] and part of the remaining tissue (~150 mg) was transferred to a homogenation buffer on ice. Isolated mitochondria (MITO) samples were prepared and used to determine respiratory capacity under different metabolic conditions. In control animals, MITO were obtained and prepared similarly immediately following anesthesia and heart removal, but without IR.
Results: In the control rats, both resting and maximally stimulated respiratory rates were higher (32 and 40%, respectively; p < 0.05) in HCR mitochondria compared to LCR. After IR, resting MITO respiratory rates were decreased to about 10% of control in both strains, and the augmented capacity in HCRs was absent. Maximally stimulated rates also were decreased more than 50% from control and were no longer different between phenotypes. Ca ⁺⁺ retention capacity and infarct size were not significantly different between HCR and LCR (49.2 ± 5.6 vs. 53.7 ± 4.9%), nor was average coronary flow during reperfusion or arrhythmogenesis. There was a significant loss of mitochondria following IR, which was coupled with decreased function in the remaining mitochondria in both strains.
Conclusion: Cardiac mitochondrial capacity from HCR was significantly higher than LCR in the controls under each condition. After IR insult, the cardiac mitochondrial respiratory rates were similar between phenotypes, as was Ca ⁺⁺ retention capacity, infarct size, and arrhythmogenicity, despite the increased mitochondrial capacity in the HCRs before ischemia. Relatively, the loss of respiratory capacity was actually greater in HCR than LCR. These data could suggest limits in the extent to which the HCR phenotype might be “protective” against acute tissue stressors. The extent to which any of these deficits could be “rescued” by adding an active exercise component to the intrinsic phenotype is unknown.
... 38 Numerous studies have provided evidence supporting that exercise training is an effective intervention which reduces myocardial I/R injury. [39][40][41] The protective effect of exercise against I/R injury was shown to be closely related to exercise-enhanced myocardial antioxidant capacity. 39 In fact, exercise was shown to reduce the infarct size after myocardial I/R injury, an effect which was abolished by suppressing SOD2. ...
... [39][40][41] The protective effect of exercise against I/R injury was shown to be closely related to exercise-enhanced myocardial antioxidant capacity. 39 In fact, exercise was shown to reduce the infarct size after myocardial I/R injury, an effect which was abolished by suppressing SOD2. 40,41 In the early phase after I/R injury, ROS production was markedly lower in the hearts of exercised mice than sedentary mice. ...
Exercise training has been widely recognized as a healthy lifestyle as well as an effective non-drug therapeutic strategy for cardiovascular diseases (CVD). Functional and mechanistic studies that employ animal exercise models as well as observational and interventional cohort studies with human participants, have contributed considerably in delineating the essential signaling pathways by which exercise promotes cardiovascular fitness and health. First, this review summarizes the beneficial impact of exercise on multiple aspects of cardiovascular health. We then discuss in detail the signaling pathways mediating exercise’s benefits for cardiovascular health. The exercise-regulated signaling cascades have been shown to confer myocardial protection and drive systemic adaptations. The signaling molecules that are necessary for exercise-induced physiological cardiac hypertrophy have the potential to attenuate myocardial injury and reverse cardiac remodeling. Exercise-regulated noncoding RNAs and their associated signaling pathways are also discussed in detail for their roles and mechanisms in exercise-induced cardioprotective effects. Moreover, we address the exercise-mediated signaling pathways and molecules that can serve as potential therapeutic targets ranging from pharmacological approaches to gene therapies in CVD. We also discuss multiple factors that influence exercise’s effect and highlight the importance and need for further investigations regarding the exercise-regulated molecules as therapeutic targets and biomarkers for CVD as well as the cross talk between the heart and other tissues or organs during exercise. We conclude that a deep understanding of the signaling pathways involved in exercise’s benefits for cardiovascular health will undoubtedly contribute to the identification and development of novel therapeutic targets and strategies for CVD.
... Epidemiologic evidence shows that there is a strong relationship between people who are training regularly and are saved from cardiac infarction [36]. Regular exercise seems to be one of the best and most effective practical and tolerable approaches to heart protection [37]. Studies in this eld showed that in various physiological conditions such as exercise and altitudes-related ischemia, and also pathological conditions (such as diseases), the concentration of SDF and other stem factors such as CSF-G, SCF, C-KIT, SCa-1 are changed [38,39]. ...
... Several studies have reported that exercise training protects against cardiac MI in animal models Induces [73,74,75,76,77]. It seems to Regular training periods one of the best and most effective and tolerant approaches that cause cardiac protection [37]. Anatomical and physiological changes in the coronary arteries, head shock protein (HSPS), increased activity of cyclooxygenase-2 (COX-2), increased endoplasmic endothelial stress (ER), enhanced potassium function of ATP-dependent sarcolemma (sarcoKATP), increased levels of ATP-dependent potassium channels in mitochondria (mitoKATP), nitric oxide (NO), and increased the antioxidant capacity of the myocardium are among the cellular-molecular mechanisms involved in cardiac protection from cardiovascular injuries [76,78]. ...
Background: One of the best and most effective applied and tolerable approaches for cardioprotecion is the regular exercise. In situation of exercise activity and even cardiac ischemic injury, the activity of the myocardial stem cells and their recruiting factors are changed so that contribute the adaptation and repairment of the myocardium. The aim of this study was to investigate the effect of myocardial preconditioning with high intensive interval training on SDF-1a myocardial levels, CXCR4 receptors and c-kit after acute myocardial infarction in male rats.
Methods: 20 male Wistar rats (8 week old ,weight 234.8 ± 5.7 g) were randomly divided into 4 groups of control (C), training (T), myocardial infraction (MI) and training+ myocardial infraction (T+MI). The training groups performed two weeks of high intensity interval training in four sections. Each section included two or three days of practice sessions and two sessions each per a day. The number or intensity of the intervals increased in each section. SDF-1, CXCR4 and C-Kit proteins were measured by the Western blot method in the myocardial tissue and myocardial injury enzymes (CK, LDH, troponin T) were measured in serum.
Results: The results of this study showed that that SDF-1, CXCR4 and C-Kit had a significant increase after two weeks of high intensity interval training and myocardial infraction. Also, serum enzyme measurements showed a positive effect of exercise, so that in the myocardium injury enzymes significantly increased in the myocardial infarction group compared with the other three groups, training and training- myocardial infarction (P<0.001). As well as, there was a significant difference between the groups of training -myocardial infarction in all of the enzymes of the myocardium injury compared to the control and training groups.
Conclusions: Even short terms of high intensity interval training can increase the levels of proteins SDF1-a, CXCR4 and C-Kit in order to cardioprotection against myocardial injury through recruitment stem cells.
... Many strategies have been considered to prevent cardiovascular diseases. However, despite a large amount of research on cardiovascular protective mechanisms, exercise is one of the most practical and effective preventive treatments, as Powers et al. [41] have ...
... Many strategies have been considered to prevent cardiovascular diseases. However, despite a large amount of research on cardiovascular protective mechanisms, exercise is one of the most practical and effective preventive treatments, as Powers et al. [41] have shown. We hypothesized that exercise regulates phenotype switching in VSMCs via the modulation of the Akt and MAKP signaling pathways. ...
The mechanisms regulating vascular smooth muscle cell (VSMC) phenotype switching and the critical signal modulation affecting the VSMCs remain controversial. Physical exercise acts as an effective drug in preventing elevated blood pressure and improving vascular function. This study was designed to explore the influence of aerobic exercise on the suppression of VSMC phenotype switching by balancing of the Akt, also known as PKB (protein kinase B) and mitogen-activated protein kinase (MAPK) signaling pathways. Spontaneously hypertensive rats (SHRs) and normotensive rats were subjected to exercise treatment before measuring the vascular morphological and structural performances. Exercise induced reverse expression of VSMC protein markers (α-SM-actin, calponin, and osteopontin (OPN)) in spontaneously hypertensive rats. It is noteworthy that the low expression of phosphorylated Akt significantly decreased the expression of VSMC contractile phenotype markers (α-SM-actin and calponin) and increased the expression of the VSMC synthetic phenotype marker (OPN). However, the MAPK signal pathway exerts an opposite effect. VSMCs and whole vessels were treated by inhibitors, namely the p-Akt inhibitor, p-ERK inhibitor, and p-p38 MAPK inhibitors. VSMC phenotype markers were reversed. It is important to note that a significant reverse regulatory relationship was observed between the expression levels of MAPK and the contractile markers in both normotensive and spontaneously hypertensive rats. We demonstrate that aerobic exercise regulates the VSMC phenotype switching by balancing the Akt and MAPK signaling pathways in SHRs.
... Another major consequence of aging is increased oxidative stress and chronic inflammation, which are major causes of tissue damages and hence induction of apoptosis, particularly in heart tissues, which works continuously and is more susceptible to oxidative stress and inflammation-induced damages [32]. Increased oxidative stress is demonstrated to induce the expression of stress sensors such as HSPs particularly HSP-70, an activating factor of cell protection signaling pathways [26]. HSP-70 is also involved in the suppression of apoptosis, hence promotion of heart survival [26,43]. ...
... Increased oxidative stress is demonstrated to induce the expression of stress sensors such as HSPs particularly HSP-70, an activating factor of cell protection signaling pathways [26]. HSP-70 is also involved in the suppression of apoptosis, hence promotion of heart survival [26,43]. ...
Aging-induced progressive decline of molecular and metabolic factors in the myocardium is suggested to be related with heart dysfunction and cardiovascular disease. Therefore, we evaluated the effects of exercise training and l-arginine supplementation on oxidative stress, inflammation, and apoptosis in ventricle of the aging rat heart. Twenty-four 24-month-aged Wistar rats were randomly divided into four groups: the aged control, aged exercise, aged l-arginine (orally administered with 150 mg/kg for 12 weeks), and aged exercise + l-arginine groups. Six 4-month-old rats were also considered the young control. Animals with training program performed exercise on a treadmill 5 days/week for 12 weeks. After 12 weeks, protein levels of Bax, Bcl-2, pro-caspase-3/cleaved caspase-3, cytochrome C, and heat shock protein (HSP)-70 were assessed. Tissue contents of total anti-oxidant capacity, superoxide dismutase, catalase, and levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, and IL-6 were analyzed. Histological and fibrotic changes were also evaluated. Treadmill exercise and l-arginine supplementation significantly alleviated aging-induced apoptosis with enhancing HSP-70 expression, increasing anti-oxidant enzyme activity, and suppressing inflammatory markers in the cardiac myocytes. Potent attenuation in apoptosis, inflammation, and oxidative stress was indicated in the rats with the combination of l-arginine supplementation and exercise program in comparison with each group (p < 0.05). In addition, fibrosis percentage and collagen accumulation were significantly lower in the rats with the combination treatment of l-arginine and exercise (p < 0.05). Treadmill exercise and l-arginine supplementation provided protection against age-induced increase in the myocyte loss and formation of fibrosis in the ventricle through potent suppression of oxidative stress, inflammations, and apoptosis pathways.
... It is well known that regular physical activity has cardioprotective effects (24,25). An active lifestyle improves the outcomes of patients with an acute myocardial infarction (26). ...
Background. Cardiac surgery, including surgical aortic valve repair (SAVR) and coronary artery bypass grafting (CABG), are associated with ischaemia-reperfusion (IR)-injury. Single bouts of exercise, including handgrip exercise, may protect against IR-injury. This study explored (I) the feasibility of daily handgrip exercise in the week prior to SAVR and/or CABG, and (II) its impact on cardiac IR-injury, measured as postoperative cardiac troponin-T (cTnT) release. Methods and Results. Sixty-five patients undergoing elective SAVR and/or CABG were randomised to handgrip exercise + usual care (intervention, n=33) or usual care alone (control, n=32). Handgrip exercise consisted of daily 4x5-min handgrip exercise (30% maximal voluntary contraction) for 2-7 days prior to cardiac surgery. Feasibility was assessed using validated questionnaires. Postoperative cTnT release was assessed at 0-6-12-18-24h (primary outcome area-under-the-curve (cTnTAUC)). Most patients (93%) adhered to handgrip exercise and 77% was satisfied with this intervention. Handgrip exercise was associated with lower cTnTAUC (402,943±225,206 versus 473,300±232,682 ng*min/L), which is suggestive for a medium effect size (Cohen's D 0.31), and lower cTnTpeak (313 [190 - 623] versus 379 [254 - 699] ng/L) compared to controls. Conclusions. We found that preoperative handgrip exercise is safe and feasible for patients scheduled for SAVR and/or CABG, and is associated with a medium effect size to reduce postoperative cardiac IR-injury. This warrants future studies to assess the potential clinical impact of exercise protocols prior to cardiac surgery.
... Rights reserved. diseases), the concentration of SDF and other stem factors such as CSF-G, SCF, C-KIT, and SCa-1 are changed (Powers et al. 2008;Ellison et al. 2011). Lu et al. showed that 1 to 2 weeks of incremental training with suitable intensity after stroke ischemia, increased levels of SDF and CXCR4. ...
One of the best and most effective applied and tolerable approaches for cardioprotection is the regular exercise. In the situation of exercise activity and even cardiac ischemic injury, the activity of the myocardial stem cells and their recruiting factors are changed so that contribute to the adaptation and repairment of the myocardium. The aim of this study was to investigate the effect of myocardial preconditioning with HIIT on SDF-1a myocardial levels, CXCR4 receptors, and c-kit after acute myocardial infarction in male rats. Twenty male Wistar were randomly divided into 4 groups: control (C), training (T), myocardial infarction (MI), and training + myocardial infarction (T + MI). The training groups performed 2 weeks of high-intensity interval training in four sections. Protein expression of SDF-1, C-Kit, and CXCR4 receptors was measured by the western blot method in the myocardial tissue, and myocardial injury enzymes were measured in serum. The results showed that SDF-1, CXCR4 receptors, and C-Kit had a significant increase after two weeks of HIIT and myocardial infarction. Also, serum enzyme measurements showed a positive effect of exercise, so that in the myocardium injury, enzymes significantly increased in the MI group compared with the other three groups (p < 0.001), and there was a significant difference between the groups of T + MI in all of the enzymes of the myocardium injury compared to the C and T groups. Even short terms of HIIT can increase the levels of proteins SDF1-a, C-Kit, and CXCR4 receptors in order to cardioprotection against myocardial injury through the recruitment of stem cells.
... Furthermore, cardiovascular disease risks can be reduced via molecular, cellular, and metabolic adaptations and oxidative stress in health and disease. [19][20][21] Baekkerud et al. detected mitochondrial dysfunction in the heart of T2DM mice, which was partly ameliorated by exercise training. 22 Despite the beneficial effects of exercise on cardiac function in patients with T2DM, the impact of optimal exercise training intensity on these patients has not been studied. ...
Type 2 diabetes mellitus (T2DM) usually develop myocardial injury and that exercise may have a positive effect on cardiac function. However, the effect of exercise intensity on cardiac function has not yet been fully examined. This study aimed to explore different exercise intensities on T2DM-induced myocardial injury. 18-week-old male mice were randomly divided into four groups: a control group, the T2DM, T2DM + medium-intensity continuous training (T2DM + MICT), and T2DM + high-intensity interval training (T2DM + HIIT) groups. In the experimental group, mice were given high-fat foods and streptozotocin for six weeks and then divided into two exercise training groups, in which mice were subjected to exercise five days per week for 24 consecutive weeks. Finally, metabolic characteristics, cardiac function, myocardial remodeling, myocardial fibrosis, oxidative stress, and apoptosis were analyzed. HIIT treatment improved cardiac function and improved myocardial injury. In conclusion, HIIT may be an effective means to guard against T2DM-induced myocardial injury.
... Specifically, studies reveal that exercise training protects the heart against arrhythmias, oxidative injury, mitochondrial damage, and cell death [33,55]. Interestingly, several investigators have shown that short-term exercise training (3-5 consecutive days) provides the same cardioprotection as that observed following long-term (10 weeks) training [34,51,52,[55][56][57]62,63,70,71]. Here, we use forced treadmill exercise which combines elements of aerobic and resistance training [22]. ...
This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic “crosstalk” to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, Ostn, had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and Ostn-KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection.
... The injury induced by myocardial IR may range from a small insult resulting in limited tissue damage to a large one leading to cellular death 3 . The ischemia may be total when the blood flow is insufficient to maintain tissue or cell life, or partial, which maintains cell viability, but with the risk of progression to cell death, depending on the tissue and time 4 . During reperfusion, with the return of mitochondrial activity and the consequent reactivation of the electron transport chain occur a large production of reactive oxygen species (ROS) and reactive nitrogen species occurs 5 . ...
Objective : In this work, rats isolated hearts were infused EPA before the ischemia period and during reperfusion for available get well in parameter relatives to redox reactions. Methods : The effect of EPA was tested on isolated hearts induced to ischemia and reperfusion, treatment occurred at different times (ischemia or reperfusion). Antioxidant capacity against peroxyl radicals, glutathione cysteine ligase activity, glutathione concentration, lactate dehydrogenase, and creatine kinase concentration was analyzed. Results : Hearts treated with eicosapentaenoic acid had the minor generation of species reactive oxygen and lipid damage after reperfusion. The GSH concentration was higher when the hearts were treated with eicosapentaenoic acid in the period of reperfusion. Conclusion : In conclusion, this study demonstrates that the dose of EPA (20μM) used before ischemia can act as a cardioprotective antioxidant molecule, prevented damage heart from ischemic and reperfusion injury.
... 74 Second, exercise leads to the sustained increase in oxygen delivery, mitochondrial content, and antioxidant capacity. 73,75 It could delay the onset of ischemia and anaerobic respiration and reduce reactive oxygen species damage in the tissues. Third, exercise is a powerful behavioral intervention that is being used in earnest to improve the immune system. ...
Objective
Preoperative exercise (prehabilitation) is commonly used as a method to reduce pain and improve function postoperatively. The purpose of this systematic review was to determine therapeutic benefits of preoperative exercise on postoperative pain, function, quality of life, and risk of complications across various types of surgeries.
Methods
Three electronic databases were used to perform a literature search. Full articles with randomized designs comparing a preoperative exercise program versus no formal program were included. The primary outcome was postoperative pain. Quality of life, function, and postoperative complications were analyzed as secondary outcomes. The primary meta-analysis was performed in those with joint replacement surgery as there were only 5 with other surgical types.
Results
A total of 28 articles were included, of which 23 were from individuals with total joint replacement surgery. Preoperative exercise resulted in lower pain ≤2 months and 3 to 5 months after joint replacement surgery with a moderate standardized mean difference (SMD [95% CI] at <2 months = −0.34 [−0.59 to −0.09]; at 3 to 5 months = −0.41 [−0.70 to −0.11]) when compared with nonexercised controls. However, ≥ 6 months after joint replacement surgery, preoperative exercise groups showed no significant differences in postoperative pain (SMD = −0.17 [−0.35 to 0.01]) when compared with nonexercised controls. Quality of life and subjective and objective function were improved ≤2 months after joint replacement surgery, but were not different ≥6 months postsurgery. Reduction in risk of postoperative complications was favored with preoperative exercise.
Conclusions
Preoperative exercise has a modest effect on postoperative pain, function, quality of life within the first 6 months after surgery and reduces the risk of developing postoperative complications in individuals undergoing joint replacement surgery. The effect of preoperative exercise on other surgery types is inconclusive.
... Genetic predisposition to obesity has been reported as a major risk factor for individuals. Considering the fact that leptin concentration is significantly increased in obese persons and is proportional to body adiposity (Gomes et al. 2012), the LEP gene have been evaluated for polymorphisms that could potentially be related to the pathophysiology of obesity and related complications (Powers et al. 2008). A considerable number of investigations have been done on the selected polymorphisms for evaluating their possible effects towards the susceptibility of obesity, but very few studies have been reported in Asian Indian population particularly in north India. ...
Leptin is an adipocyte-secreted hormone which is involved in the regulation of food intake and energy expenditure. To ascertain the potential association between leptin gene (LEP) −2548G>A and 19A>G polymorphisms and obesity risk in the north Indian Punjabi population, a group of 250 obese and 300 control subjects were randomly selected. Both the polymorphisms in the LEP gene −2548G>A (GG vs AA: odds ratio (OR), 1.44; 95% confidence interval (CI), 0.87–2.38) and 19 A>G (AA vs GG: OR, 2.31; 95% CI, 1.32–4.05) were significantly associated with an increased risk of obesity. Logistic regression analysis revealed the significant associations in a recessive genetic model (OR=2.061; 95% CI: 1.14–3.73) and (OR= 2.57; 95% CI: 1.43–4.63) respectively for −2548G>A and 19A>G polymorphisms after adjusting for various covariates of obesity, thus, confirming the major role of anthropometric and environmental factors in this population. Haplotype analysis identified that G–G haplotype conferred approximately two-fold increased obesity risk (P=0.002). The −2548A allele and the selected obesity related covariates accounted for 53%, 26% and 30.2% variability in body mass index (BMI), waist-to-hip ratio (WHR) and triglycerides (TG), respectively. Similarly, the 19G allele contributed 75%, 27% and 36% of the variability in the waist circumference (W-crc), and WHR and TG levels, respectively in the obese individuals. Therefore the present study has revealed that both LEP −2548G>A and 19A>G polymorphisms have an important role in a individual’s susceptibility towards obesity and thus could serve as relevant obesity markers in the north Indian Punjabi population.
... These changes may reduce mitochondrial biogenesis, downregulate gene levels, alter Ca 2+ and proton flux, and inevitably lead to organelle degeneration (29). Elevated intracellular Ca 2+ levels, together with other factors, lead to increased oxidative stress and the opening of mitochondrial permeability transition pores (MPTP), a process that releases proapoptotic compounds and subsequently activates caspases, resulting in mitochondrial swelling, tissue damage, and myocardial apoptosis (30). As mitochondria are finely regulated by a variety of regulatory molecules and exert a strong influence on life activities, there is an urgent need to elucidate their quality control mechanisms in detail to protect the myocardium from dysfunctional mitochondria. ...
Regular moderate-intensity exercise elicits benefit cardiovascular health outcomes. However, exhaustive exercise (EE) triggers arrhythmia, heart failure, and sudden cardiac death. Therefore, a better understanding of unfavorable heart sequelae of EE is important. Various mechanisms have been postulated for EE-induced cardiac injury, among which mitochondrial dysfunction is considered the cardinal machinery for pathogenesis of various diseases. Mitochondrial quality control (MQC) is critical for clearance of long-lived or damaged mitochondria, regulation of energy metabolism and cell apoptosis, maintenance of cardiac homeostasis and alleviation of EE-induced injury. In this review, we will focus on MQC mechanisms and propose mitochondrial pathophysiological targets for the management of EE-induced myocardial injury. A thorough understanding of how MQC system functions in the maintenance of mitochondrial homeostasis will provide a feasible rationale for developing potential therapeutic interventions for EE-induced injury.
... Altogether, we find that endurance training induces a heat shock response and HSP accumulation across tissues, which can explain some of the cytoprotective effects associated with exercise 33,34 . The alteration of HSPs primarily at the protein level illustrates the importance of measuring multiple omes to fully understand the endurance training response. ...
Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository ( https://motrpac-data.org/ ).
Highlights
Multi-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms.
Interpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise.
Robust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level.
Deep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training.
All data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages.
... Increasing evidence, including clinical trials and animal experiments, shows that moderate exercise can mediate cardiac protective role against injuries such as endothelial dysfunction [9], myocardial ischemia-reperfusion injury (IRI) [10,11], hypertension [12], heart failure [13,14], and pathological cardiac remodeling [15,16]. However, exercise training can induce the ROS production and subsequent oxidative stress, which may contribute to a series of changes that occur during exercise [17]. ...
Exercise is a preferred strategy for improving cardiac function, especially for patients with cardiovascular diseases. Increasing evidence indicates that oxidative stress is involved in exercise-induced cardioprotection, while the underlying mechanism remains unclear. Furthermore, the effect of antioxidant supplementation during or post-exercise still exists despite divergences. To explore the effect of oxidative stress and antioxidant supplementation on cardiovascular homeostasis during or post-exercise, we take insights into the progress of exercise-induced oxidative stress, antioxidant supplementation, and cardiovascular homeostasis. In particular, antioxidants such as vitamin C or E, gamma-oryzanol, and other natural antioxidants are discussed concerning regulating exercise-associated oxidative stress. Additionally, our present study reviewed and discussed a meta-analysis of antioxidant supplementation during exercise. Overall, we take an insight into the essential biological adaptations in response to exercise and the effects of antioxidant supplementation on cardiac function, which aid us in giving recommendations on antioxidant supplementation for exercisers and exercised people. A better understanding of these issues will broaden our knowledge of exercise physiology.
Graphical abstract
... High-intensity exercise without the use of music causes damage, but such damage has the potential to improve cardiac performance (Cassidy et al., 2016). Remodeling occurs after 1-5 minutes of ischemia, resulting in fibrillation without cell death in ventricular contraction performance, and ischemic and remodeling rates are at the highest when ischemic occured over 20 minutes exercise (Powers et al., 2008). High-intensity exercise will improve Cyclic Adenosine Monophosphate (cAMP). ...
Music with exercise could improve left ventricular performance, thereby decreasing the extent of tissue damage in the left ventricle of the heart. The study aimed to measure sports intervention with fast tempo music (Allegro) on the extent of cellular damage to the left ventricular myocardial tissue of the heart. This study used an experimental research design using a Random Controlled Group Posttest-Only Design. A control group was played Allegro music, a moderate sports group was played Allegro music, and a high-intensity sports group was played Allegro music using Wistar white rats of the male sex. Sport was performed using a special treadmill for mice for ten weeks. Data analysis was performed using ANOVA test. The results of this study show that there was a difference in left ventricular wall thickness in the heart between the control group and allegro music group, moderate exercise group with allegro music, and high-intensity group with allegro music (F=19,636; p=0.001). This study showed that high-intensity exercise with allegro music has the potential to improve the health of the left ventricle of the heart.
... Hearts were removed immediately and held at − 20 °C for 20 min. The heart was cut transversely to a millimeter of thickness using a rat heart matrix and the heart slices immersed in 2,3,5 triphenyltetrazolium chloride (TTC, Sigma-Aldrich, St Louis, MO, USA) for 20 min at 37 °C and then fixed in 10% formaldehyde [18,19]. After 24 h, the heart slices were scanned. ...
The formation of new blood vessels in the ischemic area is a fundamental strategy that can reduce myocardial infarction-induced damage by mitigating hypoxia. This paper set out to investigate the cardioprotective effect of high-intensity interval training preconditioning and L-arginine supplementation on myocardial ischemia–reperfusion-induced angiogenesis and oxidative stress. 50 male rats were randomly distributed into following groups: (1) Sham, (2) Sedentary control (Con, n = 10), 3) L-arginine treatment (La, n = 10), (4) High-Intensity Interval Training (HIIT, n = 10), and High-Intensity Interval Training plus L-arginine supplementation (HIIT + La, n = 10). Rats in the training groups performed high-intensity interval training for 8 weeks (5 day per week). Subjects in La and HIIT + La groups received L-arginine in drinking water (4 g/L). 72 h after treatments, all subjects underwent myocardial ischemia–reperfusion operation. Cardiac function, angiogenesis, stress oxidative, and infarction size were measured after reperfusion. Results showed exercise training and L-arginine supplementation promoted Cat and GSH activities and decreased MDA activity following myocardial ischemia–reperfusion injury in non-infarcted area. Compared with the con group, VEGF and Ang-1 as well as Ang-1 to Ang-2 ratio following myocardial ischemia–reperfusion in the non-infarct area were higher in La + HIIT group. Meanwhile, capillary density and capillary-to-muscle fiber ratio were higher in response to training and L-arginine supplementation. HIIT and L-arginine alone and synergistically decreased ischemia–reperfusion-induced infarction size. Cardiac output and stroke volume ameliorate in response to exercise training and L-arginine supplementation. Taken together, exercise preconditioning and l-arginine supplementation improved left ventricular function following ischemia–reperfusion by stress oxidative mitigation and angiogenesis amelioration.
... Physical exercise has many positive effects on cardiovascular health. Exercise training protects the myocardium against ischemia-reperfusion injury, reduces myocardial oxidative damage and improves cardiac function after IRI onset [343][344][345]. Various factors derived from the heart and other tissues are responsible for this effect, but much remains to be clarified. ...
The majority of cardiovascular deaths are associated with acute coronary syndrome, especially ST-elevation myocardial infarction. Therapeutic reperfusion alone can contribute up to 40 percent of total infarct size following coronary artery occlusion, which is called ischemia-reperfusion injury (IRI). Its size depends on many factors, including the main risk factors of cardiovascular mortality, such as age, sex, systolic blood pressure, smoking, and total cholesterol level as well as obesity, diabetes, and physical effort. Extracellular vesicles (EVs) are membrane-coated particles released by every type of cell, which can carry content that affects the functioning of other tissues. Their role is essential in the communication between healthy and dysfunctional cells. In this article, data on the variability of the content of EVs in patients with the most prevalent cardiovascular risk factors is presented, and their influence on IRI is discussed.
... Exercise training is a kind of mechanical and stress stimulation. Human epidemiological studies have shown that regular exercise can reduce the risk of death during myocardial ischemia-reperfusion injury [72]. Meanwhile, the studies in animal models have also shown that regular endurance exercise (running or swimming training) may mimic the favorable cardioprotective effect of ischemia preconditioning and attenuate cardiomyocyte death under the circumstance of myocardial ischemia-reperfusion injury [73][74][75][76]. ...
Cardiovascular diseases (CVDs) are a group of common disorders associated with heart and its blood vessels, with the characteristics of high incidence or high mortality and poor prognosis, especially for elderly population. CVD is the leading cause of global mortality and the dominant contributor for reduced quality of life among people with chronic diseases all over the world. CVDs are usually composed of hypertension, atherosclerosis, cardiomyopathy, myocardial ischemia–reperfusion injury, and other complications. According to the statistics from the WHO report in 2017, approximately 17.8 million people are died of CVDs each year, accounting for 31% of all deaths worldwide, and CVDs could result in 35.6 million people lived with disability [1]. Obesity, drug abuse, hyperlipidemia, high blood pressure, reduced physical activity, smoking, and alcohol drinking are important factors for inducing CVDs. The current incidence of CVDs shows a rapidly increasing trend, which could result in the significant impact on the quality of life of these patients and the larger burden on social and medical system.
... Exercise training is considered beneficial to the cardiovascular system. Regular physical exercise has been shown to improve physical health, improve cardiac function and strengthen the cellular mechanisms that prevent cardiac damage [21][22][23]. Regular exercise throughout the life reduces cardiovascular diseases and improves functional ability [24]. Studies have shown that voluntary exercise throughout the life can improve age-related gene expression changes in the heart, suggesting that exercise can maintained the heart young [25]. ...
Aging is the most important risk factor for cardiovascular diseases. Although exercise is known to be beneficial for the health of aging heart, the optimal exercise training intensity to prevent natural aging-induced cardiac damage has not been defined. In this study, we used 32-week-old male mice and randomly divided them into three groups, namely, untrained (UNT) mice, moderate-intensity exercise training (MET) mice, and high-intensity interval training (HIIT) mice. Mice in the two exercise training groups were subjected to exercise 5 days per week for 24 consecutive weeks. Metabolic characteristics, cardiac function and morphology, myocardial remodeling, myocardial fibrosis (collagen III, α-SMA, and TGF-β), oxidative stress (NRF2, HO-1, SOD, and NOX4), and apoptosis (BAX, Bak, Bcl-2, and Bcl-XL) were analyzed 24 weeks after the different treatments. MET improved cardiac function and reduced myocardial remodeling, myocardial fibrosis, and oxidative stress in the aging heart. MET treatment exerted an anti-apoptotic effect in the heart of the aging mice. Importantly, HIIT did not protect against cardiac damage during the natural aging process. These findings suggest that MET may be one of the main methods to prevent cardiac damage induced by natural aging.
... Beneficial impacts of exercise on cardiovascular structure and function are also seen in CVD, such as ischemia-reperfusion injury (IRI) and chronic heart failure (CHF). Endurance exercise has been reported to reduce oxidative stress and structural damage in IRI, thereby preventing myocardial dysfunction in animal studies [87][88][89][90][91][92]. However, the role of biological sex (if any) on the effects of exercise on myocardial oxidative stress is not clear. ...
Cardiovascular diseases (CVD) remain the leading cause of death in men and women. Biological sex plays a major role in cardiovascular physiology and pathological cardiovascular remodeling. Traditionally, pathological remodeling of cardiovascular system refers to the molecular, cellular, and morphological changes that result from insults, such as myocardial infarction or hypertension. Regular exercise training is known to induce physiological cardiovascular remodeling and beneficial functional adaptation of the cardiovascular apparatus. However, impact of exercise-induced cardiovascular remodeling and functional adaptation varies between males and females. This review aims to compare and contrast sex-specific manifestations of exercise-induced cardiovascular remodeling and functional adaptation. Specifically, we review (1) sex disparities in cardiovascular function, (2) influence of biological sex on exercise-induced cardiovascular remodeling and functional adaptation, and (3) sex-specific impacts of various types, intensities, and durations of exercise training on cardiovascular apparatus. The review highlights both animal and human studies in order to give an all-encompassing view of the exercise-induced sex differences in cardiovascular system and addresses the gaps in knowledge in the field.
... En effet, il est aujourd'hui largement décrit que l'exercice régulier réduit le risque de décès lors de l'IR myocardique en augmentant les défenses enzymatiques antioxydantes (MnSOD, Cu-ZnSOD et GPx) (Hamilton et al., 2001;Powers et al., 1998). Ceci serait notamment expliqué par l'activation du facteur nucléaire de transcription Nrf2 en réponse au stress oxydant aigu produit par chaque exercice physique (Done and Traustadóttir, 2016;Lee et al., 2012b;Powers et al., 2008). Dans notre travail, en accord avec des études précédentes , nous observons une diminution de la production d'ERO au cours de la reperfusion post-ischémique dans les coeurs d'animaux entrainés. ...
L’infarctus du myocarde constitue la première cause de mortalité cardiovasculaire. A ce jour, la seule stratégie permettant de limiter la mort cellulaire au cours de l’ischémie cardiaque est la reperfusion. Néanmoins, elle est à l’origine de lésions qui lui sont propres. L’établissement d’un cercle vicieux entre la surproduction d’espèces réactives oxygénées mitochondriales (EROmt) et la surcharge calcique (Ca2+) matricielle semble être un acteur clé de l’exacerbation de la mort cellulaire dans les premiers instants de la reperfusion. Dans ce contexte, l’objectif de ce travail de thèse a été de développer et/ou de mieux comprendre les mécanismes sous-jacents de stratégies naturelles permettant de limiter l’établissement de ce cercle vicieux pour permettre une protection des mitochondries au cours de l’ischémie-reperfusion. Notre première stratégie a été d’identifier dans la nature des molécules antioxydantes dont les propriétés physico-chimiques permettent de cibler le stress oxydant mitochondrial. Nous avons pu identifier un antioxydant naturel, la sinapine dont les propriétés chimiques pourraient lui conférer un tropisme mitochondrial. On a ainsi pu démontrer in vitro, in cellulo, ex vivo et in vivo que la sinapine était capable de cibler le stress oxydant mitochondrial et ainsi diminuer la sensibilité du cœur à l’IR. La deuxième étude de ce travail de thèse consistait à mieux identifier les mécanismes cellulaires sous-jacents à la cardioprotection par l’exercice physique. Une attention toute particulière a été portée sur le rôle clé joué par la signalisation du monoxyde d’azote (NO) au niveau mitochondrial. En effet, le NO est bien décrit comme pouvant moduler la production d’EROmt et comme permettant de protéger le cœur au cours de l’IR. Néanmoins, à ce jour, l’impact de l’exercice sur la signalisation eNOS-NO au niveau mitochondrial est mal connu. Nous avons pu observer qu’un entraînement modéré de 5 semaines était à l’origine d’une translocation de la eNOS au niveau des mitochondries et que celle-ci était associée à une augmentation de la biodisponibilité du NO au niveau mitochondrial et à une modification du s-nitrosoprotéome. Enfin, nous avons pu montrer que la S-nitrosylation joue un rôle clé dans la protection des mitochondries en situation de stress permettant de mimer l’ischémie-reperfusion. Mots
... Regular physical activity is important not only for mental health but also for physical health. Exercise training has implications in epigenetic regulation [1], aging [2], improvement of glycemic control in patients with type 2 diabetes mellitus and insulin sensitivity and resistance [3,4], prevention of cardiovascular diseases [5][6][7], and others such as multiple sclerosis, lung diseases, Parkinson's disease, and so on [8][9][10][11][12][13]. Thus, the study of lipid metabolism is a key element to understand how physical activity influences our health and, in particular, that of professional athletes. ...
Since the lipid profile is altered by physical activity, the study of lipid metabolism is a remarkable element in understanding if and how physical activity affects the health of both professional athletes and sedentary subjects. Although not fully defined, it has become clear that resistance exercise uses fat as an energy source. The fatty acid oxidation rate is the result of the following processes: (a) triglycerides lipolysis, most abundant in fat adipocytes and intramuscular triacylglycerol (IMTG) stores, (b) fatty acid transport from blood plasma to muscle sarcoplasm, (c) availability and hydrolysis rate of intramuscular triglycerides, and (d) transport of fatty acids through the mitochondrial membrane. In this review, we report some studies concerning the relationship between exercise and the aforementioned processes also in light of hormonal controls and molecular regulations within fat and skeletal muscle cells.
... Besides the alteration of general cardiovascular risk factors (e.g., high blood pressure or hypercholesterolemia), exercise confers direct protection against I/R injury of a distant organ. This protective effect may include the development of collateral arteries, alterations in circulation, expression of endoplasmic reticulum stress proteins, and the modulation of cyclooxygenase-2 activity, heat shock proteins, and ATP-sensitive potassium channels [14,15]. Exercise also induces antioxidant effects [16][17][18] and diminishes the increased susceptibility of cardiac mitochondria to undergo permeability transition pore opening [19]. ...
There is a growing body of evidence showing the importance of physical activity against acute ischemic events in various organs. Ischemia/reperfusion injury (I/R) is characterized by tissue damage as a result of restriction and subsequent restoration of blood supply to an organ. Oxidative stress due to increased reactive oxygen species formation and/or insufficient antioxidant defense is considered to play an important role in I/R. Physical activity not only decreases the general risk factors for ischemia but also confers direct anti-ischemic protection via myokine production. Myokines are skeletal muscle-derived cytokines, representing multifunctional communication channels between the contracting skeletal muscle and other organs through an endocrine manner. In this review, we discuss the most prominent members of the myokines (i.e., brain-derived neurotrophic factor (BDNF), cathepsin B, decorin, fibroblast growth factors-2 and-21, follistatin, follistatin-like, insulin-like growth factor-1; interleukin-6, interleukin-7, interleukin-15, irisin, leukemia inhibitory factor, meteorin-like, myonectin, musclin, myostatin, and osteoglycin) with a particular interest in their potential influence on reactive oxygen and nitrogen species formation or antioxidant capacity. A better understanding of the mechanism of action of myokines and particularly their participation in the regulation of oxidative stress may widen their possible therapeutic use and, thereby, may support the fight against I/R.
... Continuation of exercise beyond that point might put the subject at risk of developing myocardial ischaemia and angina pectoris (173). Although numerous studies have reported that exercise preconditioning is associated with increasing tolerance to I/R injury (174)(175)(176)(177)(178), the maximal hypoxic exercise often disrupts the prooxidant-antioxidant balance in myocardial tissue and potentially jeopardizes cardiac functions. Additionally, heavy exercise causes ischaemia associated ventricular arrhythmias (179). ...
Exercise conducted at an optimum training load is usually beneficial for the overall health of an individual. However, an unaccustomed intense exercise carried out by untrained individuals or elite athletes during over-training and/or competition-related stress often bear inevitable cardiovascular risks. Although many alterations occurring in the cardiovascular system during exercise are the results of training adaptations, sudden cardiovascular deaths reported in competitive athletes is a matter of grave concern. Several oxidative biomarkers that depict the underlying structural and functional impairment of the myocardial tissue have been identified in the individuals subjected to extensive exercise. The exercise-mediated cardiomyopathy is free radical related and also associated with pro-inflammatory response. In this review we will highlight the possible role of melatonin in obviating irrevocable oxidative cardiovascular injury triggered by extensive exercise stress. Melatonin effectively reduces exercise-induced lipid peroxidation, restores natural cellular antioxidant pool and supresses the innate immune cascade reaction that, otherwise, jeopardize cardiovascular integrity. Melatonin blocks the IKK/IκB/NFκB signaling as well as suppress iNOS and COX-2 mediated inflammation in cardiac tissue. In addition, melatonin reduces blood lactate accumulation and accelerates glucose utilization, thereby, promoting energy metabolism in athletes during their training and competition. Physical exertion associated overheating and the resultant sympathetic outflow impede cardiovascular homeostasis. Melatonin not only attenuates the sympathomedullary stimulation but also protects the cardiac cells from the cytotoxic effect of catecholamines. The available information regarding the efficacy of melatonin in amelioration of exercise-driven oxidative insult in cardiac tissue has been discussed and summarized.
... Regular exercise has been recognized as an effective method to improve heart function and reduce cardiovascular disease and mortality. Different animal models and human epidemiological studies suggest that exercise can have significant cardioprotective effects [22][23][24]. These protective mechanisms can be listed as maximum oxygen consumption, improvements in cardiorespiratory capacity, lipid profile and endothelial functions, as well as increases in mitochondrial antioxidant capacity and the number of capillaries [25]. ...
The effects of swimming exercise on age-associated electrical changes in female rat hearts were investigated. Four- and 24-month-old Wistar female rats were divided into three groups as follows: sedentary young, sedentary old and exercise old. Swimming exercise was performed for 8 weeks (60 min/day, 5 days/week). All recordings were taken from freshly isolated left ventricular myocytes of rat heart. Aging caused a significant increase in the size of myocytes; swimming exercise did not affect this change. The repolarization period of the action potential was prolonged in aged myocytes, but exercise training had no effect on this prolongation. Exercise suppressed the transient outward potassium currents, while the inactivation and reactivation kinetics did not change between the groups. Moreover, aging caused suppression in the inward rectifier potassium currents, and exercise increased this suppression. Consequently, changes in the action potential and potassium currents may contribute to the impaired cardiac function in the elderly female myocardium, and swimming exercise is not an effective strategy in reversing these electrical changes.
... The HSP family, especially HSP72, is believed to provide myocardial protection against increased ROS generation during I/R events [39,40]. HSP72 is strongly activated during I/R insults and triggers a counter-regulatory action against cellular oxidative damage by modulating the SOD [40] and CAT [41] activities. ...
... Such increase of adipose tissue TG lipolysis and, presumably, IMTG, is mediated by increased catecholamine response to exercise (6). Exercise training has implications in the improvement of glycemic control in patients with type 2 diabetes mellitus and insulin sensitivity and resistance (9,42) and in the prevention of multiple sclerosis, lung diseases, Parkinson's disease, and cardiovascular diseases (31,82). Physical activity is associated with reduced cardiovascular morbidity and mortality (21,35,81) and is recommended for treatment of hyperlipidemia, which is known for being a risk of coronary heart disease (CHD) (17,66). ...
Blood lipoproteins are formed by various amounts of cholesterol (C), triglycerides (TG), phospholipids and apolipoproteins (Apos). Apo A1 is the major structural protein of high-density lipoprotein (HDL), accounting for approximately 70% of HDL protein, and mediates many of the anti-atherogenic functions of HDL. Conversely, Apo B is the predominant low-density lipoprotein (LDL) Apo and is a reliable indicator of circulating LDL, associated with higher coronary heart disease (CHD) risk. Furthermore, the Apo B/Apo A1 ratio is used as a surrogate marker of the risk of CHD related to lipoproteins. Elevated or abnormal levels of lipids and/or lipoproteins in the blood is a significant CHD risk factor and several studies strongly support the idea that aerobic exercise decreases CHD risk partially lowering serum TG and LDL-cholesterol (LDL-C) levels and increasing HDL-C levels. Exercise also exerts an effect on HDL-C maturation and composition and on reverse C transport from peripheral cells to the liver, in order to favor its catabolism and excretion. This process prevents atherosclerosis and several studies showed that exercise training increases heart lipid metabolism and protects against cardiovascular disease. The purpose of this review is to assess the effects of endurance training on the nontraditional lipid biomarkers including Apo B, Apo A1, Apo B/Apo A1 ratio in CHD.
... There are several examples of this in our profession. [2][3][4][5][6] There are also many physical therapists around the world actively engaged in these areas of research, and some are international leaders in their respective fields of basic science and applied physiology. [2][3][4][7][8][9][10][11][12][13][14][15][16][17] Despite the efforts of these research leaders, many in our profession continue to hold these views toward basic and applied physiological research. ...
... Therefore, the relaxation response to diazoxide (a K ATP channel activator) increases significantly, and the vasoconstriction response to glibenclamide (a K ATP channel inhibitor) becomes markedly suppressed [44,45]. As a result, upregulated protein expression of Kir6.1 after exercise shortens myocardial tissue oxygenation recovery time and protects the heart against I/R injury [58]. ...
Myogenic contraction of vascular smooth muscle cells (VSMCs) in resistance arteries and arterioles plays a critical role in regulating peripheral resistance. Ion channels expressed in VSMCs control ion influx or efflux from the plasma membrane and endoplasmic reticulum to regulate membrane potential, which contributes to the regulation of vascular tone. With the depolarization of VSMC membranes, an elevation of intracellular calcium ion (Ca²⁺) concentration is mediated by voltage-gated Ca²⁺ channels and can trigger a vasoconstrictive response. In addition, potassium ion (K⁺) efflux through K⁺ channels can hyperpolarize VSMCs, resulting in vasodilation. However, in the pathophysiological progression of diseases such as hypertension, VSMCs undergo a wide range of pathological changes, among them is “electrical remodeling”, which refers to changes in ion channels. Under physiological or pathological conditions, exercise has a profound impact on the human body, and ion channels are an essential target of the beneficial adaptive responses. This review provides insight on the physiological function of ion channels in VSMCs, including CaV1.2 channels, voltage-gated K⁺ channels, large-conductance Ca²⁺-activated K⁺ channels, and inward-rectifier K⁺ channels, and the changes of these ion channels during hypertension. Focus is given to the effects of exercise on these ion channels and its implications in disease treatment.
Background
Liver transplantation stands as the primary treatment for end-stage liver disease, with demand surging in recent decades because of expanded indications. However, hepatic ischemia/reperfusion injury can lead to liver transplant failure in both deceased donor and living donor transplantation. This study explored whether preconditioning donor livers through exercise training (ExT) could mitigate cold ischemic injury posttransplantation.
Methods
Donor C57BL/6 mice underwent ExT via treadmill running or remained sedentary. After 4 wk, the donor liver underwent cold storage and subsequent orthotopic liver transplantation or ex vivo warm reperfusion.
Results
Donor liver from mice subjected to ExT showed significantly decreased hepatic injury on reperfusion. Tissue histology revealed decreased sinusoidal congestion, vacuolization, and hepatocellular necrosis in livers from ExT mice, and immunofluorescence staining further revealed a decreased number of apoptotic cells in ExT grafts. Livers from ExT donors expressed decreased intragraft inflammatory cytokines cascade, decreased neutrophil infiltration and neutrophil extracellular traps, and increased M2 phenotype of recipient macrophages compared with grafts from sedentary mice. After cold storage, liver grafts from ExT donors showed decreased accumulation of reactive oxygen species and decreased levels of cytochrome c and high mobility group box 1 released in the liver effluent. In addition, ExT grafts showed upregulated peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and higher levels of mitochondrial content. Similar effects of decreased hepatic injury were observed in wild-type mice when pretreated with a PGC-1α stimulator ZLN005 instead of ExT.
Conclusions
These findings suggest that augmenting hepatocytic mitochondrial content through donor exercise or PGC-1α stimulation may offer therapeutic avenues to mitigate postreperfusion inflammation and improve transplant outcomes.
Human and animal studies have demonstrated the mechanisms and benefits of aerobic exercise for both cardiovascular and neurovascular health. Aerobic exercise induces neuroplasticity and neurophysiologic reorganization of brain networks, improves cerebral blood flow, and increases whole-body VO2peak (peak oxygen consumption). The effectiveness of a structured cardiac rehabilitation (CR) program is well established and a vital part of the continuum of care for people with cardiovascular disease. Individuals post stroke exhibit decreased cardiovascular capacity which impacts their neurologic recovery and extends disability. Stroke survivors share the same risk factors as patients with cardiac disease and can therefore benefit significantly from a comprehensive CR program in addition to neurorehabilitation to address their cardiovascular health. The inclusion of individuals with stroke into a CR program, with appropriate adaptations, can significantly improve their cardiovascular health, promote functional recovery, and reduce future cardiovascular and cerebrovascular events thereby reducing the economic burden of stroke.
The study of exercise preconditioning can develop strategies to prevent cardiovascular diseases and outline the efficient exercise model. However, the exercise type with the most protective effect against ischemia-reperfusion injury is unknown. In this study, we examined the effects of three kinds of exercise preconditioning on myocardial ischemia-reperfusion in adult rats and explored the possible underlying mechanisms. Male Wistar rats subjected to ten weeks of endurance, resistance, and concurrent training underwent ischemia (30 min) and reperfusion (120 min) induction. Then, infarction size, serum levels of the CK-MB, the redox status, and angiogenesis proteins (VEGF, ANGP-1, and ANGP-2) were measured in the cardiac tissue. Results showed that different exercise training modes have the same reduction effects on infarction size, but ischemia-reperfusion-induced CK-MB was lower in response to endurance training and concurrent training. Furthermore, cardiac VEGF levels increased in all three kinds of exercise preconditioning but ischemia-reperfusion-induced ANGP-1 elevated more in endurance training. The cardiac GPX activity was improved significantly through the resistance and concurrent exercise compared to the endurance exercise. In addition, all three exercise preconditioning models decreased MPO levels, and ischemia reperfusion-induced MDA was lower in endurance and resistance training. Overall, these results indicated that cardioprotection of exercise training against ischemia-reperfusion injury depends on the exercise modality. Cardioprotective effects of aerobic, resistance, and concurrent exercises are due to different mechanisms. The preconditioning effects of endurance training are mediated mainly by pervasive angiogenic responses and resistance training through oxidative stress amelioration. The preconditioning effects of concurrent training rely on both angiogenesis and oxidative stress amelioration.
In recent years, a growing body of research has demonstrated that an individual’s fitness level is a strong and independent marker of risk for cardiovascular and all-cause mortality. In addition, modest improvements in fitness through exercise intervention have been associated with considerable health outcome benefits. These studies have generally assessed fitness as a baseline marker in traditional epidemiological cohorts. However, there has been a recent recognition that fitness powerfully predicts outcomes associated with a wide range of surgical interventions. The concept of "prehabilitation" is based on the principle that patients with higher functional capability will better tolerate a surgical intervention, and studies have shown that patients with higher fitness have reduced postoperative complications and demonstrate better functional, psychosocial, and surgery-related outcomes. This review focuses on the impact of fitness on surgical outcomes and provides a rationale in support of routine application of prehabilitation in the management of patients undergoing surgery.
Purpose
This study evaluates the association between habitual physical activity (HPA) and the outcomes of patients with myocardial infarction (MI).
Methods
Patients newly diagnosed with MI were divided into two groups based on whether they engaged in HPA, defined as an aerobic activity with a duration of no less than 150 min/week, before the index admission. The primary outcomes included major adverse cardiovascular events (MACEs), cardiovascular (CV) mortality, and cardiac readmission rate 1 year following the index date of admission. A binary logistic regression model was applied to analyze whether HPA was independently associated with 1-year MACEs, 1-year CV mortality, and 1-year cardiac readmission rate.
Results
Among the 1,266 patients (mean age 63.4 years, 72% male), 571 (45%) engaged in HPA, and 695 (55%) did not engage in HPA before MI. Patients who participated in HPA were independently associated with a lower Killip class upon admission (OR = 0.48: 95% CI, 0.32–0.71, p < 0.001) and a lower prevalence of 1-year MACEs (OR = 0.74: 95% CI, 0.56–0.98, p = 0.038) and 1-year CV mortality (OR = 0.50: 95% CI, 0.28–0.88, p = 0.017) than those who did not participate in HPA. HPA was not associated with cardiac-related readmission (OR = 0.87: 95% CI, 0.64–1.17, p = 0.35).
Conclusions
HPA before MI was independently associated with a lower Killip class upon admission, 1-year MACEs, and 1-year CV mortality rate.
The obesity due to high caloric ingestion is related to the accumulation of body fat andpredisposes cardiovascular diseases. Recent studies about the High Intensity Interval Training(HIIT) evidence benefits of its practice in patients that maybe carrying this disease, mainlybecause of the reduction of comorbidities associated with obesity. This present study has theobjective of evaluating the HIIT effects on the adipocytes’ changes of the epicardium adiposetissue in fat animals induced by the consumption of high-fat diet. It was used male rats ofWistar lineage fed daily with HFD and trained by HIIT three times a week for 8 consecutiveweeks. The animals were weighted during the training sections and, after its euthanasia, wererealized histological analyses of the epicardium adipose tissue. The results showed that HFDincreased the body weight of the animals and the side view of the adipocytes. However, theHIIT did not change the area of the adipocytes of the epicardial adipose tissue, even thoughthe diet had been a hypertrophy factor of this tissue. Then, we can conclude that HIITcontributes to avoid the body weight gain but was not capable of reducing the area of theadipocytes of the epicardium adipose tissue.
The main pathological manifestation of coronary artery disease is myocardial injury caused by ischemia-reperfusion (IR) injury. Regular exercise reduces the risk of death during myocardial IR injury. The aim of this study was to describe the effects of various types of exercise on myocardial IR injury. Four electronic databases PubMed, Web of Science, Embase, and Cochrane Library were comprehensively searched from inception until February 2022, to identify studies relevant to the current review, using the method of combining subject and free words. Finally, 16 articles were included in the meta-analysis. Results showed that exercise training decreases the Myocardial infarct size compared to the control group (SMD = -2.6, 95 % CI [-3.53 to -1.67], P < 0.01); increasing the coronary blood flow (MD = 2.93, 95 % CI [2.41 to 3.44], P < 0.01), left ventricular developed pressure (SMD = 2.28, 95 % CI [0.12 to 4.43], P < 0.05), cardiac output (SMD = 1.22, 95 % CI [0.61 to 1.83], P < 0.01) compared to the control group. According to the descriptive analysis results also showed that exercise training increases the left ventricular ejection fraction, superoxide dismutase, manganese superoxide dismutase, glutathione peroxidase, copper-zinc superoxide dismutase, glutathione peroxidase, and decrease the creatine kinase, creatine kinase-MB, lactate dehydrogenase, Malondialdehyde, cardiac troponins T. Exercise can improve myocardial function after myocardial IR injury; however, further research is needed in combination with specific issues such as exercise mode, intensity, duration, and model issues.
Objective
Cardiac mitochondrial dysfunction was found in ischemic heart disease (IHD). Hence, this study determined the effects of exercise training (ET) on cardiac mitochondrial respiration and cardiac mitochondrial quality control in IHD.
Methods
A narrative synthesis was conducted after searching animal studies written in English in three databases (PubMed, Web of Science, and EMBASE) until December 2020. Studies that used aerobic exercise as an intervention for at least 3 weeks and had at least normal, negative (sedentary IHD), and positive (exercise-trained IHD) groups were included. The CAMARADES checklist was used to check the quality of the included studies.
Results
The 10 included studies (CAMARADES score: 6–7/10) used swimming or treadmill exercise for 3–8 weeks. Seven studies showed that ET ameliorated cardiac mitochondrial respiratory function as manifested by decreased reactive oxygen species (ROS) production and increased complexes I-V activity, superoxide dismutase 2 (SOD2), respiratory control ratio (RCR), NADH dehydrogenase subunits 1 and 6 (ND1/6), Cytochrome B (CytB), and adenosine triphosphate (ATP) production. Ten studies showed that ET improved cardiac mitochondrial quality control in IHD as manifested by enhanced and/or controlled mitochondrial biogenesis, dynamics, and mitophagy. Four other studies showed that ET resulted in better cardiac mitochondrial physiological characteristics.
Conclusion
Exercise training could improve cardiac mitochondrial functions, including respiration, biogenesis, dynamics, and mitophagy in IHD.
Systematic review registration
https://www.crd.york.ac.uk/prospero/ display_record.php?RecordID=226817 , identifier: CRD42021226817.
Myocardial disorders are the most common cause of renal failure and mortality in diabetic patients, but the molecular mechanism of this process is not yet clear. The reduction of nuclear Erythroid2-related factor-2 (Nrf-2) and positive regulators of Nrf-2 proteins, such as DJ-1 and microRNA-126 (miR-126), after hypoxia and the promotion of reactive oxygen species, might be an intervention indicator in renal failure after myocardial ischemia-reperfusion. Therefore, this study evaluates the renoprotective effect of exercise training and Crataegus persica extract (CE) on myocardial ischemia-reperfusion-induced kidney injury in diabetic rats. Fifty rats were divided into five groups: healthy sedentary control (Con), sedentary diabetic (D), interval trained diabetic (TD), diabetic plus Crataegus persica extract treatment (CD), and interval trained diabetic plus Crataegus persica extract treatment (TCD) groups. The rats in the exercise groups were subjected to moderate-intensity interval training five days per week for ten weeks. The rats in CD and TCD groups received 300 mg/kg of Crataegus persica through gavage for ten weeks. Then, the subjects underwent 30 min of myocardial ischemia and subsequently reperfusion for 24 h. At the end of the experiment, insulin sensitivity, oxidative stress, renal function, histopathology of the kidney, Nrf-2, miR-126, and DJ-1 gene expression levels were evaluated. The results show that the treatments decreased elevated levels of renal oxidative stress, glomerular filtration rate, insulin sensitivity, and pathological score in diabetic rats. Also, the expression of Nrf-2 and miR-126, unlike DJ-1, decreased in diabetic rats due to interval training. Due to the results, diabetes aggravates acute myocardial ischemia-reperfusion-induced kidney injury, while moderate-intensity interval training and Crataegus persica treatment simultaneously ameliorate myocardial ischemia-reperfusion-induced renal injury via miR-126/Nrf-2 pathway and improve insulin sensitivity and renal function in type 1 diabetic rats.
Background
Aging decreases ischemic tolerance, while exercise prevents myocardial ischemia reperfusion (IR) injury. The cardioprotective role of high intensity interval training (HIIT), however, is unknown.
Methods
Accordingly, we investigated 8 weeks (5 days/week, 40 min/day) of HIIT treadmill exercise (60%/90% of VO2 peak) on IR injury in young (2-month) and senescent (20-month) Wistar rat myocardia (N = 10/group). Surgical IR (30 min/120 min) was performed via reversible left anterior descending artery ligation and ECG was analyzed to determine ventricular ectopy during IR period.
Results
Infarction size and oxidative stress were measured in hearts post-mortem. Glutathione peroxidase activity and Myeloperoxidase levels were mitigated with age, but elevated post IR. HIIT potentiated antioxidant defenses in young and old hearts, and infarction size was lower in young HIIT trained. Metrics of reactive oxygen species were not lower after IR, and were not affected by HIIT in young or old rats. Ventricular ectopy score in senescent rats was insignificantly more than young rats and HIIT significantly decreased ventricular ectopy score in young and senescent rats.
Conclusions
Findings indicate that IR tolerance is mitigated in senescent hearts, while HIIT ameliorated infarction by increasing antioxidant enzymes activity in young and senescent hearts.
Effect of Six Weeks of Moderate-Intensity Endurance Training on Serum
Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene
(FGF23) in the Hearts of Diabetic Rats: An Experimental Study
L. Bolboli1, M. Khajehlandi2
Received: 28/03/21 Sent for Revision: 24/04/21 Received Revised Manuscript: 15/05/21 Accepted: 16/05/21
Background and Objectives: Diabetic patients are highly susceptible to cardiovascular involvement. Therefore, the
aim of the present study was to determine the effect of six weeks of moderate-intensity endurance training on serum
levels of Klotho and expression of the fibroblast-23 growth factor (FGF23) gene in the hearts of diabetic rats.
Materials and Methods: In this experimental study, 21 adult male Wistar rats were randomly divided into three groups
of seven: diabetic training group (DT), diabetic control group (DC), and healthy control group (HC). Diabetes was
induced by intraperitoneal injection of Streptozotocin (STZ). Animals performed moderate-intensity endurance
training for six weeks. Serum levels of Klotho and FGF23 gene expression in the heart tissue were evaluated by Elisa
method and real time PCR, respectively. Data were analyzed by one-way analysis of variance and Scheffe’s post hoc
test.
Results: The findings showed that after six weeks of training, blood glucose concentration (mg/dl) in the DT group
was significantly lower than the DC group (p=0.001), and serum levels of Klotho (ng/ml) was significantly increased
compared to the DC (p=0.032), but there was no significant difference between the DT and DC groups in the expression
of FGF23 gene (relative expression) (p=0.171).
Conclusion: The results suggested that moderate-intensity endurance training has a positive effect on the serum levels
of Klotho and blood glucose, and it appears to be somewhat protective of heart function.
Key words: Klotho, FGF23, Endurance training, Diabetes, Heart, Rat
Funding: This study was funded by University of Mohaghegh Ardabili.
Conflict of interest: None declared.
Ethical approval: The Ethics Committee of Ardabil University of Medical Sciences approved the study
(IR.ARUMS.REC.1398.251).
How to cite this article: Bolboli L, Khajehlandi M. The Effect of Six Weeks of Moderate-Intensity Endurance
Training on Serum Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene (FGF23) in the Hearts
of Diabetic Rats: An Experimental Study. J Rafsanjan Univ Med Sci 2021; 20 (4): 371-86. [Farsi]
1 - Associate Prof., Dept. of Exercise Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil,
Iran, ORCID: 0000-0002-7981-4343
(Corresponding Author) Tel: (045) 33520457, Fax: (045) 33520457, E-mail: l_bolboli@uma.ac.ir
2 - PhD Candidate, Dept. of Exercise Physiology, Faculty of Educational Sciences and Psychology, University of Mohaghegh Ardabili, Ardabil,
Background and Objectives: Diabetic patients are highly susceptible to cardiovascular involvement. Therefore, the aim of the present study was to determine the effect of six weeks of moderate-intensity endurance training on serum levels of Klotho and expression of the fibroblast-23 growth factor (FGF23) gene in the hearts of diabetic rats.
Materials and Methods: In this experimental study, 21 adult male Wistar rats were randomly divided into three groups of seven: diabetic training group (DT), diabetic control group (DC), and healthy control group (HC). Diabetes was induced by intraperitoneal injection of Streptozotocin (STZ). Animals performed moderate-intensity endurance training for six weeks. Serum levels of Klotho and FGF23 gene expression in the heart tissue were evaluated by Elisa method and real time PCR, respectively. Data were analyzed by one-way analysis of variance and Scheffe’s post hoc test.
Results: The findings showed that after six weeks of training, blood glucose concentration (mg/dl) in the DT group was significantly lower than the DC group (p=0.001), and serum levels of Klotho (ng/ml) were significantly increased compared to the DC (p=0.032), but there was no significant difference between the DT and DC groups in the expression of FGF23 gene (relative expression) (p=0.171).
Conclusion: The results suggested that moderate-intensity endurance training has a positive effect on the serum levels of Klotho and blood glucose, and it appears to be somewhat protective of heart function.
Keywords: Klotho, FGF23, Endurance training, Diabetes, Heart, Rat
Funding: This study was funded by the University of Mohaghegh Ardabili.
Conflict of interest: None declared.
Ethical approval: The Ethics Committee of Ardabil University of Medical Sciences approved the study (IR.ARUMS.REC.1398.251).
How to cite this article: Bolboli L, Khajehlandi M. The Effect of Six Weeks of Moderate-Intensity Endurance Training on Serum Levels of Klotho and Expression of the Fibroblast-23 Growth Factor Gene (FGF23) in the Hearts of Diabetic Rats: An Experimental Study. J Rafsanjan Univ Med Sci 2021; 20 (4): 371-86. [Farsi]
Keywords: Klotho, FGF23, Endurance training, Diabetes, Heart, Rat
Cardiovascular disease (CVD) is potentiated by risk factors including physical inactivity and remains a leading cause of morbidity and mortality. Although regular physical activity (PA) does not reverse atherosclerotic coronary disease, precursory exercise improves clinical outcomes in those experiencing life-threatening CVD events. Exercise preconditioning describes the cardioprotective phenotype whereby even a few exercise bouts confer short-term multifaceted protection against acute myocardial infarction. First described decades ago in animal investigations, cardioprotective mechanisms responsible for exercise preconditioning have been identified through reductionist preclinical studies, including the upregulation of endogenous antioxidant enzymes, improved calcium handling, and enhanced bioenergetic regulation during a supply-demand mismatch. Until recently, translation of this research was only inferred from clinically-directed animal models of exercise involving ischemia-reperfusion injury, and reinforced by the gene products of exercise preconditioning that are common to mammalian species. However, recent clinical investigations confirm that exercise preconditions the human heart. This discovery means that simply the initiation of a remedial exercise regimen in those with abnormal CVD risk factor profiles will provide immediate cardioprotective benefits and improved clinical outcomes following acute cardiac events. In conclusion, the prophylactic biochemical adaptations to aerobic exercise are complemented by the long-term adaptive benefits of vascular and architectural remodeling in those who adopt a physically active lifestyle.
PURPOSE: Exercise improve myocardial cell protection and vascular function through cell repair and suppression of oxidative stress in cardiovascular diseases caused by aging. This study aimed to investigate the effect of combine exercise on HSP70 and SOD1 protein expression of aorta, skeletal muscle and myocardium in high fat diet induced obese aging rats.METHODS: Male 50-week-old Sprague Dawley rats (n=40) were divided into normal diet (ND, n=10), normal diet+exercise (NDEx, n=10), high fat diet (HFD, n=10), and high fat diet+exercise (HFDEx, n=10) groups. After six weeks on a high fat diet to induce obesity, a 12-week combine exercise program was implemented, which combine exercise (treadmill running+ladder climbing) three times a week for 45 minutes per session.RESULTS: Body weight was significantly decreased after 12 weeks combine exercise program compared to the ND group (p<.05) and HFDEx group compared to the HFD group (p<.05), respectively. After completing the 12-week exercise program, heat shock protein 70 (HSP70) and superoxide dismutase 1 (SOD1) expressions were significantly (p<.05) higher in the NDEx group compared to the ND group in the myocardium. Also, SOD1 protein expression was significantly (p<.05) higher in the NDEx group compared to the ND group and HFDEx group compared to the HFD group in the skeletal muscle.CONCLUSIONS: In conclusion, combine exercise intervention of high fat diet-induced obesity resulted in decreased cell repair protein and antioxidant enzyme protein in the myocardium. Therefore, it is thought that combine exercise intervention for obese induced rats improved the cell repair protein and antioxidant enzyme activity of the myocardium.
Aim
We investigated the effects of high-intensity interval and continuous short-term exercise on body composition and cardiac function after myocardial ischemia-reperfusion injury (IRI) in obese rats.
Methods
Rats fed with a standard chow diet (SC) or high-fat diet (HFD) for 20 weeks underwent systolic blood pressure (SBP), glycemia and dual-energy X-ray absorptiometry analyses. Then, animals fed with HFD were subdivided into three groups: sedentary (HFD-SED); moderate-intensity continuous training (HFD-MICT); and high-intensity interval training (HFD-HIIT). Exercised groups underwent four isocaloric aerobic exercise sessions, in which HFD-MICT maintained the intensity continuously and HFD-HIIT alternated it. After exercise sessions, all groups underwent global IRI and myocardial infarct size (IS) was determined histologically. Fat and muscle mass were weighted, and protein levels involved in muscle metabolism were assessed in skeletal muscle.
Results
HFD-fed versus SC-fed rats reduced lean body mass by 31% (P < 0.001), while SBP, glycemia and body fat percentage were increased by 10% (P = 0.04), 30% (P = 0.006) and 54% (P < 0.001); respectively. HFD-induced muscle atrophy was restored in exercised groups, as only HFD-SED presented lower gastrocnemius (32%; P = 0.001) and quadriceps mass (62%; P < 0.001) than SC. PGC1-α expression was 2.7-fold higher in HFD-HIIT versus HFD-SED (P = 0.04), whereas HFD-HIIT and HFD-MICT exhibited 1.7-fold increase in p-mTORSer2481 levels compared to HFD-SED (P = 0.04). Although no difference was detected among groups for IS (P = 0.30), only HFD-HIIT preserved left-ventricle developed pressure after IRI (+0.7 mmHg; P = 0.9).
Significance
Short-term exercise, continuous or HIIT, restored HFD-induced muscle atrophy and increased mTOR expression, but only HIIT maintained myocardial contractility following IRI in obese animals.
Background The FOXO3a/Beclin-1 pathway is an important pathway in autophagy that can be impaired in diabetic patients who are prone to cardiomyopathy.
Objective The aim of this study was to investigate the effect of an 8-week endurance training program on the content of FOXO3a and Beclin-1 proteins in the heart muscle tissue of rats with type 2 diabetes.
Methods This experimental study was conducted on 12 male two-month-old Sprague Dawley rats with a mean weight of 270±20 g. After diabetic induction by streptozotocin and nicotinamide, rats were randomly assigned into two groups of diabetic-exercise (n=6) and diabetic-control (n=6). The diabetic-exercise group received intervention 4 days per week, each session for 42 minutes at a speed of 10-30 m/m for 8 weeks, while the control group received no any training program. The rats did not receive any insulin treatment during the study. Collected data were analyzed using independent t-test at a significance level of P≤0.05.
Findings No significant changes were observed in the content of FOXO3a (P=0.12) and Beclin-1 (P=0.34) proteins in the training group compared to the control group after intervention.
Conclusion The endurance training can not affect the content of FOXO3a and Beclin-1 proteins. Therefore, it seems that endurance training may not affect autophagy signaling in the heart muscle of type 2 diabetic patients.
New findings:
What is the central question of this study? Can a short-term of HIIT contribute to the reduction of IR injury by enhancing the levels of Klotho and its related axes, including myocardial TRPC6 expression, and antioxidant defense as novel possible mechanisms to EICP against IR injury? What is the main finding and its importance? The increasing of plasma and myocardial levels of Klotho as a result of preconditioning with HIIT and preventing a significant reduction of Klotho during IR injury can promote cardioprotection and reduce damage by attenuate the myocardial TRPC6 expression and increased antioxidant defense. Present findings may provide a new mechanism in EICP and IR injury, and Provides the knowledge to develop preventive and therapeutic approaches.
Abstract:
Cardiovascular disease, especially coronary artery disease remains a major cause of morbidity and mortality in the world and ischemia-reperfusion (IR) insult is the main pathologic cause leads to death during these diseases. Exercise training is associated with a reduced risk of cardiovascular disease and cardioprotection development against IR injury. Therefore, the purpose of this study was to investigate the effect of preconditioning with high-intensity interval training on myocardial and plasma levels of klotho and its related axes as novel mechanisms to exercise-induced cardioprotection against IR injury. Seventy male Wistar rats were randomly divided into 5 groups of Control, HIIT, Sham, IR, and H-IR. The training group performed 5 sessions of high intensity interval training on the treadmill. The cardiac IR injury was induced by LAD ligation for 30 min followed by 24 h reperfusion. Infarct size and histopathological assessment of cardiac tissues were determined through Evans Blue-TTC and H&E staining respectively. We investigated lipid peroxidation and markers of cardiac injury, antioxidant enzymes, and the plasma levels of klotho using the ELISA assay. Also, myocardial levels of Klotho and TRPC6 expression was determined by western blot assay. The results demonstrated a significant increase in myocardial and plasma levels of Klotho following HIIT and a significant decrease during IR injury. The myocardial TRPC6 channels expression increased following IR. The HIIT also prevented a significant reduction of the Klotho during IR and consequently reduced the expression of TRPC6 channel in the H-IR group compared the IR group. Furthermore, HIIT decreased the infarct size, cardiac injury, lipid peroxidation, LDH, CK-MB, and cTnI and improved TAC, CAT, SOD, GPx activities and antioxidant system following IR injury. The findings of the present study suggest that HIIT improves cardioprotection against IR injury and reduces cardiac damages through an increase in myocardial and plasma levels of klotho and its related axes (TRPC6 and antioxidant defense). These findings can help to develop preventive and therapeutic approaches. This article is protected by copyright. All rights reserved.
Electron paramagnetic resonance spectroscopy has been applied to measure radical generation in the postischemic heart; however, there is controversy regarding the methods used and the conclusion as to whether radicals are generated. In order to resolve this controversy, direct and spin trapping measurements of the time course and mechanisms of radical generation were performed in isolated perfused rabbit hearts. In reperfused tissue, 3 prominent radical signals are observed: A, isotropic g = 2.004 suggestive of a semiquinone; B, anisotropic g parallel = 2.033 and g perpendicular = 2.005 suggestive of ROO.; and C, a triplet g = 2.000 and aN = 24 G suggestive of a nitrogen centered radical. B and C, however, are highly labile and disappear at temperatures probably encountered in some previous studies. In normally perfused hearts, A is observed with only small amounts of B and C. During ischemia, B and C increase reaching a maximum after 45 min while A decreases. On reflow with oxygenated perfusate all 3 signals increase. With varying duration of ischemia and reflow, peak signal intensities occurred after 15 s of reflow following 30 min of ischemia. Reperfusion with superoxide dismutase, deferoxamine, or mannitol abolished the reperfusion increase of B. Measurements performed with the spin trap 5,5'-dimethyl-1-pyrroline-N-oxide (DMPO) demonstrated a similar time course of radical generation with prominent DMPO-OH and DMPO-R signals peaking between 10 and 20 s of reflow. Superoxide dismutase and deferoxamine also quenched these signals. Thus, .O2- derived .OH, R., and ROO. radicals are generated in postischemic myocardium. While the experimental techniques used can result in loss of intrinsic radicals and generation of extraneous radicals, with proper care and controls valid measurements of free radicals in biological tissues can be performed.
Controversy exists as to the effect of endurance training on myocardial antioxidant enzyme activity. These experiments sought to clarify this issue by examining antioxidant enzyme activities in the rat ventricular myocardium in response to different intensities and durations of exercise training. Female Fischer-344 rats (120 days old) were assigned to either a sedentary control group or one of nine exercise training groups. Animals were exercised on a motorized treadmill for 10 wk; combinations of three durations (30, 60, and 90 min/day), and three levels of exercise intensity (low, moderate, and high) were studied. Exercise training did not alter (P > 0.05) citrate synthase, catalase, or glutathione peroxidase activities in the right or left ventricle. In contrast, high-intensity exercise (all durations) and moderate-intensity exercise (90 min/day) resulted in a significant increase (P < 0.05; +28-30%) in right ventricular superoxide dismutase (SOD) activity. Similarly, high-intensity exercise training (all durations) resulted in a significant elevation (P < 0.05; +14-26%) of left ventricular SOD activity. Furthermore, low- and moderate-intensity exercise training of long duration (i.e., 60-90 min/day) resulted in significant increases (P < 0.05; +10-23%) in left ventricular SOD activity. These data support the hypothesis that high-intensity exercise (> or = 30 min/day) or moderate-intensity exercise of long duration (> or = 60 min/day) is effective in upregulating SOD activity in the ventricular myocardium.
It is well known that physical training permits an animal to respond successfully to exercise loads of various types, intensities, and durations. Furthermore, the trained animal can sustain the activity for a long period before the fatigue becomes limiting. The effects of physical training on the antioxidant defenses of tissues and on their susceptibility to damage induced by exhaustive exercise have been investigated. Therefore, untrained rats were sacrificed either at rest or immediately after swimming to exhaustion. Rats trained to swim for 10 weeks were also sacrificed, 48 hr after the last exercise, either at rest or after exhaustive swimming. Homogenates of liver, heart, and muscle were used for biochemical determinations. Mitochondrial and sarcoplasmic (SR) or endoplasmic (ER) reticulum integrity was assessed with measurements of respiratory control index and latency of alkaline phosphatase activity. Lipid peroxidation was measured by determination of malondialdehyde and hydroperoxides. Additionally, the effect of training on the antioxidant protection systems of tissues was examined by determining the glutathione peroxidase and glutathione reductase activity and the overall antioxidant capacity. Mitochondrial, SR, and ER integrity and lipid peroxidation were similar in trained and untrained at rest animals, whereas the glutathione peroxidase and glutathione reductase activity and the overall antioxidant capacity of tissues were greater in trained animals. The exhaustive exercise gave rise to tissue damage irrespective of the trained state, as documented by similar loss of SR and ER integrity, and by increase in lipid peroxidation found in exhausted trained and untrained rats. Because exercise endurance capacity was greatly increased by training, our results suggest that free radical-induced damage in muscle could be one of the factors terminating muscle effort. In effect, the greater antioxidant level should allow trained muscle to withstand oxidative processes more effectively, thus lengthening the time required so that the cell function is sufficiently damaged as to make further exercise impossible.
Experimental studies examining the effects of regular exercise on cardiac responses to ischemia and reperfusion (I/R) are limited. Therefore, these experiments examined the effects of endurance exercise training on myocardial biochemical and physiological responses during in vivo I/R. Female Sprague-Dawley rats (4 mo old) were randomly assigned to either a sedentary control group or to an exercise training group. After a 10-wk endurance exercise training program, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 20 min, followed by a 10-min period of reperfusion. Compared with untrained, exercise-trained animals maintained higher (P < 0.05) peak systolic blood pressure throughout I/R. Training resulted in a significant (P < 0.05) increase in ventricular nonprotein thiols, heat shock protein (HSP) 72, and the activities of superoxide dismutase (SOD), phosphofructokinase (PFK), and lactate dehydrogenase. Furthermore, compared with untrained controls, left ventricles from trained animals exhibited lower levels (P < 0. 05) of lipid peroxidation after I/R. These data demonstrate that endurance exercise training improves myocardial contractile performance and reduces lipid peroxidation during I/R in the rat in vivo. It appears likely that the improvement in the myocardial responses to I/R was related to training-induced increases in nonprotein thiols, HSP72, and the activities of SOD and PFK in the myocardium.
Oxidative stress causes cardiac damage following ischemia/reperfusion and in response to anthracyclines. Extracellular signal-regulated kinases (ERK) 1/2 are activated by oxidative stress in cardiac myocytes and protect cardiac myocytes from apoptosis. Prostaglandins (PG) also protect cells from injury in a number of tissues, including the cardiomyocyte. Cyclooxygenase (COX) the rate-limiting enzyme in PG biosynthesis has two isoforms, the constitutive COX-1 and an inducible COX-2. Here, we examined the effects of two oxidative stresses, hydrogen peroxide (H2O2) and the anthracycline doxorubicin on the activity of ERK1/2 and the expression of COX isoforms and PG formation in neonatal rat primary cardiomyocytes. These cells expressed COX-1 at rest and both COX isoforms on treatment with phorbol 12-myristate 13-acetate. Exposure to 50 microM H2O2 for 10 min or doxorubicin at 10 and 100 micrograms/ml caused expression of COX-2 that was prevented by free radical scavengers. COX-2 induction was associated with activation of ERK1/2 and the specific ERK-inhibitor PD098059 abolished COX-2 expression. Treatment of cells with decoy oligonucleotides corresponding to COX-2 promoter elements implicated the AP-1 and NF-kappaB-2 but not the NF-kappaB-1 in the transcription of COX-2. Induction of COX-2 mRNA and protein was accompanied by increased prostacyclin formation, which was abolished by the selective COX-2 inhibitor, NS-398, and PD098059. H2O2 and doxorubicin enhanced the release of lactate dehydrogenase and free radical scavengers prevented this. NS-398 enhanced the release of lactate dehydrogenase in response to H2O2 and doxorubicin, whereas the injury was prevented by iloprost, a stable prostacyclin analogue. In cardiomyocytes cell injury by H2O2 and doxorubicin is limited by an increase in prostacyclin formation that reflects induction of COX-2 mediated by ERK1/2 activation.
Epidemiologic investigations have shown that exercise reduces morbidity and mortality from coronary artery disease. In this study, using a rat model, we attempted to determine whether exercise can reduce ischemic injury to the heart and elucidate a mechanism for the cardioprotective effect of exercise. Results showed that exercise significantly reduced the magnitude of a myocardial infarction in biphasic manner. The time course for cardioprotection resembled that of the change in manganese superoxide dismutase (Mn-SOD) activity. The administration of the antisense oligodeoxyribonucleotide to Mn-SOD abolished the expected decrease in infarct size. We showed that the level of tumor necrosis factor alpha (TNF-alpha) and interleukin 1beta (IL-1beta) increased after exercise. The simultaneous administration of the neutralizing antibodies to the cytokines abolished the exercise-induced cardioprotection and the activation of Mn-SOD. Furthermore, TNF-alpha can mimic the biphasic pattern of cardioprotection and activation of Mn-SOD. An antioxidant completely abolished cardioprotection and the activation of Mn-SOD by exercise or the injection of TNF-alpha as well as exercise-induced increase in TNF-alpha and IL-1beta. The production of reactive oxygen species and endogenous TNF-alpha and IL-1beta induced by exercise leads to the activation of Mn-SOD, which plays major roles in the acquisition of biphasic cardioprotection against ischemia/reperfusion injury in rats.
This study investigates the apoptotic activity of the cyclooxygenase-2 (COX-2) inhibitor celecoxib in prostate carcinoma cells. COX-2 is constitutively expressed in androgen-responsive LNCaP and androgen-nonresponsive PC-3 cells. Exposure of these cells to celecoxib induces characteristic features of apoptosis, including morphological changes, DNA laddering, and caspase-3 activation, whereas piroxicam, a COX-1-specific inhibitor, displays no appreciable effect on either cancer cell line even after prolonged exposure. Moreover, the potency of celecoxib in apoptosis induction is significantly higher than that of other COX-2 inhibitors examined despite the observation that these inhibitors exhibit similar IC(50) in COX-2 inhibition. It is noteworthy that normal human prostate epithelial cells, expressing a marginally detectable level of COX-2, are insensitive to the induction of apoptosis by celecoxib. These data suggest a correlation between COX-2 expression and sensitivity to the apoptotic effect of the COX-2 inhibitor. In an effort to delineate the underlying mechanism, we examined the effect of celecoxib on the expression of Bcl-2 as well as the activation of the key anti-apoptotic kinase Akt. In contrast to an earlier report that attributed the apoptotic activity of NS398 in LNCaP cells to Bcl-2 down-regulation, we provide evidence that the induction of apoptosis by celecoxib in LNCaP and PC-3 cells is independent of Bcl-2. First, treatment with celecoxib does not alter the cellular Bcl-2 level in both cell lines. Second, enforced Bcl-2 expression in PC-3 cells does not confer protection against the induction of apoptosis by celecoxib. Our data show that celecoxib treatment blocks the phosphorylation of Akt. This correlation is supported by studies showing that overexpression of constitutively active Akt protects PC-3 cells from celecoxib-induced apoptosis. Nevertheless, how celecoxib down-regulates Akt is not clear because the drug does not adversely affect phosphoinositide 3-kinase activity in vivo and okadaic acid, a protein phosphatase 2A inhibitor, cannot rescue the inhibition. In summary, our data demonstrate that inhibition of Akt activation may play a crucial role in the induction of apoptosis by celecoxib.
Previous studies have shown that myocytes isolated from sedentary (Sed) rat hearts 3 wk after myocardial infarction (MI) undergo hypertrophy, exhibit altered intracellular Ca(2+) concentration ([Ca(2+)](i)) dynamics and abnormal contraction, and impaired sarcoplasmic reticulum (SR) function manifested as prolonged half-time of [Ca(2+)](i) decline. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca(2+) regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would restore [Ca(2+)](i) dynamics and SR function in MI myocytes toward normal. In MI rats, HIST ameliorated myocyte hypertrophy as indicated by significant (P </= 0.05) decreases in whole cell capacitances [Sham-Sed 179 +/-12 (n = 20); MI-Sed 226 +/- 7 (n = 20); MI-HIST 183 +/- 11 pF (n = 19)]. HIST significantly (P < 0.0001) restored both systolic [Ca(2+)](i) [Sham-Sed 421 +/- 9 (n = 79); MI-Sed 350 +/- 6 (n = 70); MI-HIST 399 +/- 9 nM (n = 70)] and half-time of [Ca(2+)](i) decline (Sham-Sed 0. 197 +/- 0.005; MI-Sed 0.247 +/- 0.006; MI-HIST 0.195 +/- 0.006 s) toward normal. Compared with Sham-Sed myocytes, SR Ca(2+)-ATPase expression significantly (P < 0.001) decreased by 44% in MI-Sed myocytes. Surprisingly, expression of SR Ca(2+)-ATPase was further reduced in MI-HIST myocytes to 26% of that measured in Sham-Sed myocytes. There were no differences in calsequestrin expression among the three groups. Expression of phospholamban was not different between Sham-Sed and MI-Sed myocytes but was significantly (P < 0.01) reduced in MI-HIST myocytes by 25%. Our results indicate that HIST instituted shortly after MI improves [Ca(2+)](i) dynamics in surviving myocytes. Improvement in SR function by HIST is mediated not by increased SR Ca(2+)-ATPase expression, but by modulating phospholamban regulation of SR Ca(2+)-ATPase activity.
We examined the role of cyclooxygenase-2 (COX-2) in the late phase of ischemic preconditioning (PC). A total of 176 conscious rabbits were used. Ischemic PC (six cycles of 4-min coronary occlusions/4-min reperfusions) resulted in a rapid increase in myocardial COX-2 mRNA levels (+231 +/- 64% at 1 h; RNase protection assay) followed 24 h later by an increase in COX-2 protein expression (+216 +/- 79%; Western blotting) and in the myocardial content of prostaglandin (PG)E(2) and 6-keto-PGF(1alpha) (+250 +/- 85% and +259 +/- 107%, respectively; enzyme immunoassay). Administration of two unrelated COX-2 selective inhibitors (NS-398 and celecoxib) 24 h after ischemic PC abolished the ischemic PC-induced increase in tissue levels of PGE(2) and 6-keto-PGF(1alpha). The same doses of NS-398 and celecoxib, given 24 h after ischemic PC, completely blocked the cardioprotective effects of late PC against both myocardial stunning and myocardial infarction, indicating that COX-2 activity is necessary for this phenomenon to occur. Neither NS-398 nor celecoxib lowered PGE(2) or 6-keto-PGF(1alpha) levels in the nonischemic region of preconditioned rabbits, indicating that constitutive COX-1 activity was unaffected. Taken together, these results demonstrate that, in conscious rabbits, up-regulation of COX-2 plays an essential role in the cardioprotection afforded by the late phase of ischemic PC. Therefore, this study identifies COX-2 as a cardioprotective protein. The analysis of arachidonic acid metabolites strongly points to PGE(2) and/or PGI(2) as the likely effectors of COX-2-dependent protection. The recognition that COX-2 mediates the antistunning and antiinfarct effects of late PC impels a reassessment of current views regarding this enzyme, which is generally regarded as detrimental.
The purpose of these experiments was to examine the effects of dietary antioxidant supplementation with vitamin E (VE) and alpha-lipoic acid (alpha-LA) on biochemical and physiological responses to in vivo myocardial ischemia-reperfusion (I-R) in aged rats. Male Fischer-334 rats (18 mo old) were assigned to either 1) a control diet (CON) or 2) a VE and alpha-LA supplemented diet (ANTIOX). After a 14-wk feeding period, animals in each group underwent an in vivo I-R protocol (25 min of myocardial ischemia and 15 min of reperfusion). During reperfusion, peak arterial pressure was significantly higher (P < 0.05) in ANTIOX animals compared with CON diet animals. I-R resulted in a significant increase (P < 0.05) in myocardial lipid peroxidation in CON diet animals but not in ANTIOX animals. Compared with ANTIOX animals, heart homogenates from CON animals experienced significantly less (P < 0.05) oxidative damage when exposed to five different in vitro radical producing systems. These data indicate that dietary supplementation with VE and alpha-LA protects the aged rat heart from I-R-induced lipid peroxidation by scavenging numerous reactive oxygen species. Importantly, this protection is associated with improved cardiac performance during reperfusion.
Apoptosis is a coordinated sequence of events culminating in the death of the cell. Many of these biochemical processes are regulated by the mitochondria, including the release of proapoptotic molecules in addition to the caspase-activating cofactor, cytochrome c. Pro- and antiapoptotic members of the Bcl-2 family regulate mitochondrial participation in cell death. Current models explaining cytochrome c release are discussed in light of mitochondrial structure and physiology.
We examined the effects of 3 days of exercise in a cold environment on the expression of left ventricular (LV) heat shock proteins (HSPs) and contractile performance during in vivo ischemia-reperfusion (I/R). Sprague-Dawley rats were divided into the following three groups (n = 12/group): 1) control, 2) exercise (60 min/day) at 4 degrees C (E-Cold), and 3) exercise (60 min/day) at 25 degrees C (E-Warm). Left anterior descending coronary occlusion was maintained for 20 min, followed by 30 min of reperfusion. Compared with the control group, both the E-Cold and E-Warm groups maintained higher (P < 0.05) LV developed pressure, first derivative of pressure development over time (+dP/dt), and pressure relaxation over time (-dP/dt) throughout I/R. Relative levels of HSP90, HSP72, and HSP40 were higher (P < 0.05) in E-Warm animals compared with both control and E-Cold. HSP10, HSP60, and HSP73 did not differ between groups. Exercise increased manganese superoxide dismutase (MnSOD) activity in both E-Warm and E-Cold hearts (P < 0.05). Protection against I/R-induced lipid peroxidation in the LV paralleled the increase in MnSOD activity whereas lower levels of lipid peroxidation were observed in both E-Warm and E-Cold groups compared with control. We conclude that exercise-induced myocardial protection against a moderate duration I/R insult is not dependent on increases in myocardial HSPs. We postulate that exercise-associated cardioprotection may depend, in part, on increases in myocardial antioxidant defenses.
These experiments examined the independent effects of short-term exercise and heat stress on myocardial responses during in vivo ischemia-reperfusion (I/R). Female Sprague-Dawley rats (4 mo old) were randomly assigned to one of four experimental groups: 1) control, 2) 3 consecutive days of treadmill exercise [60 min/day at 60-70% maximal O2 uptake (VO2 max)], 3) 5 consecutive days of treadmill exercise (60 min/day at 60-70% VO2 max), and 4) whole body heat stress (15 min at 42 degrees C). Twenty-four hours after heat stress or exercise, animals were anesthetized and mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was maintained for 30-min followed by a 30-min period of reperfusion. Compared with control, both heat-stressed animals and exercised animals (3 and 5 days) maintained higher (P < 0.05) left ventricular developed pressure (LVDP), maximum rate of left ventricular pressure development (+dP/dt), and maximum rate of left ventricular pressure decline (-dP/dt) at all measurement periods during both ischemia and reperfusion. No differences existed between heat-stressed and exercise groups in LVDP, +dP/dt, and -dP/dt at any time during ischemia or reperfusion. Both heat stress and exercise resulted in an increase (P < 0.05) in the relative levels of left ventricular heat shock protein 72 (HSP72). Furthermore, exercise (3 and 5 days) increased (P < 0.05) myocardial glutathione levels and manganese superoxide dismutase activity. These data indicate that 3-5 consecutive days of exercise improves myocardial contractile performance during in vivo I/R and that this exercise-induced myocardial protection is associated with an increase in both myocardial HSP72 and cardiac antioxidant defenses.
The past two decades have witnessed an explosive growth of knowledge regarding postischemic myocardial dysfunction or myocardial “stunning.” The purpose of this review is to summarize current information regarding the pathophysiology and pathogenesis of this phenomenon. Myocardial stunning should not be regarded as a single entity but rather as a “syndrome” that has been observed in a wide variety of experimental settings, which include the following: 1) stunning after a single, completely reversible episode of regional ischemia in vivo; 2) stunning after multiple, completely reversible episodes of regional ischemia in vivo; 3) stunning after a partly reversible episode of regional ischemia in vivo (subendocardial infarction); 4) stunning after global ischemia in vitro; 5) stunning after global ischemia in vivo; and 6) stunning after exercise-induced ischemia (high-flow ischemia). Whether these settings share a common mechanism is unknown. Although the pathogenesis of myocardial stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen-derived free radicals (oxyradical hypothesis) and by a transient calcium overload (calcium hypothesis) on reperfusion. The final lesion responsible for the contractile depression appears to be a decreased responsiveness of contractile filaments to calcium. Recent evidence suggests that calcium overload may activate calpains, resulting in selective proteolysis of myofibrils; the time required for resynthesis of damaged proteins would explain in part the delayed recovery of function in stunned myocardium. The oxyradical and calcium hypotheses are not mutually exclusive and are likely to represent different facets of the same pathophysiological cascade. For example, increased free radical formation could cause cellular calcium overload, which would damage the contractile apparatus of the myocytes. Free radical generation could also directly alter contractile filaments in a manner that renders them less responsive to calcium (e.g., oxidation of critical thiol groups). However, it remains unknown whether oxyradicals play a role in all forms of stunning and whether the calcium hypothesis is applicable to stunning in vivo. Nevertheless, it is clear that the lesion responsible for myocardial stunning occurs, at least in part, after reperfusion so that this contractile dysfunction can be viewed, in part, as a form of “reperfusion injury.” An important implication of the phenomenon of myocardial stunning is that so-called chronic hibernation may in fact be the result of repetitive episodes of stunning, which have a cumulative effect and cause protracted postischemic dysfunction. A better understanding of myocardial stunning will expand our knowledge of the pathophysiology of myocardial ischemia and provide a rationale for developing new therapeutic strategies designed to prevent postischemic dysfunction in patients.
Heat shock proteins (HSPs) play a critical role in maintaining cellular homeostasis and protecting cells during episodes of acute stress. Specifically, HSPs of the 70 kDa family (i.e.. HSP72) are important in preventing ischemia-reperfusion induced apoptosis. necrosis. and oxidative injury in a variety of cell types including the cardiac myocyte. Evidence indicates that HSP72 may contribute to cellular protection against a variety of stresses by preventing protein aggregation. assisting in the refolding of damaged proteins, and chaperoning nascent polypeptides along ribosomes. Endurance exercise is a physiological stress that can be used to elevate myocardial levels of HSP72. It is now clear that endurance exercise training can elevate myocardial HSP72 by 400-500%% in young adult animals. Importantly, an exercise-induced elevation in myocardial HSPs is associated with a reduction in ischemia-reperfusion (I-R) injury in the heart. Although it seems likely that exercise-induced elevations in myocardial levels of HSPs play an important role in this protection against an I-R insult, new evidence suggests that other factors may also be involved. This is an important area for future research.
[GRAPHICS] Palladium-mediated coupling/intramolecular indole cyclization of terminal alkynes with resin 8, followed by cleavage of the sulfonamide linkage, were executed under mild conditions to provide diverse indoles 10 in excellent yield and purity. This chemistry benefits from a dual activation process that derives from use of a traceless N-sulfonyl linker. Also, direct mercuration of 9 (X = H, R = 4-Me-C6H4), followed by palladium mediated coupling with methyl acrylate, efficiently provided I functionalized product 12.
We examined the effects of two exercise training modalities, i.e., low-intensity endurance and sprint running, on in vitro, isovolumic myocardial performance following ischemia and reperfusion. Rats ran on a treadmill 5 d·wk-1 for 6 wk at the following levels: endurance; 20 m·min-1, 0% grade, 60 min·d-1 and sprint; five 1-min runs at 75 m·min-1, 15% grade interspersed with 1-min active recovery runs at 20 m·min-1, 15% grade. Both endurance and sprint training significantly improved exercise tolerance relative to control (P < 0.05) on two graded exercise tests. Buffer perfused hearts of control (N = 18), endurance (N = 20), and sprint(N = 13) trained animals underwent no-flow ischemia (20 min) and reperfusion (30 min) in a Langendorff mode. During reperfusion, left ventricular developed pressure and its first derivative were 20% higher in sprint (P < 0.05) than either endurance or control hearts. Left ventricular end-diastolic pressure was lowest in sprint during reperfusion(sprint, 10 ± 1 mm Hg vs endurance, 14 ± 2 mm Hg; and control, 14 ± 2 mm Hg, at 30 min reperfusion). Hearts were then used for biochemical studies or dissociated into single cells for measurement of contraction, cell calcium, and action potential duration. Single cell contractions were greatest in sprint despite similar calcium transients in all groups. Ischemia/reperfusion caused action potential prolongation in control but not trained myocytes. Hearts from sprint had the greatest glycer-aldehyde-3-phosphate dehydrogenase activity (P < 0.05) and a tendency towards increased superoxide dismutase activity. These results suggest that sprinting increases myocardial resistance to ischemia/ reperfusion. This protection may be secondary to increased myofilament calcium sensitivity and/or myocardial expression of glyceraldehyde-3-phosphate dehydrogenase.
Aerobic exercise training induces an increase in coronary blood flow capacity that is associated with altered control of coronary vascular resistance and, therefore, coronary blood flow. The relative importance of metabolic, myogenic, endothelium-mediated, and neurohumoral control systems varies throughout the coronary arterial tree, and these control systems contribute in parallel to regulating coronary vascular resistance to differing degrees at each level in the coronary arterial tree. In addition to this nonuniformity of the relative importance of vascular control systems in the coronary arterial tree, it appears that exercise training-induced adaptations are also distributed spatially, in a nonuniform manner throughout the coronary tree. As a result, it is necessary to examine training-induced adaptations throughout the coronary arterial tree. Adaptations in endothelium-mediated control play a role in training-induced changes in control of coronary vascular resistance, and there is evidence that the effects of training may be different in large coronary arteries than in the microcirculation. Also, there is evidence that the mode, frequency, and intensity of exercise training bouts and duration of training may influence the adaptive changes in endothelial function. Exercise training has also been shown to induce changes in responses of coronary vascular smooth muscle to vasoactive agents and alterations in the cellular-molecular control of intracellular Ca2+ in coronary vascular smooth muscle of conduit coronary arteries and to enhance myogenic reactivity of coronary resistance arteries. Exercise training also appears to have different effects on vascular smooth muscle in large coronary arteries than in the microcirculation. For example, adenosine sensitivity is increased in conduit coronary arteries and large resistance arteries after training but is not altered in small coronary resistance arteries of trained animals. Although much remains to be studied, evidence clearly indicates that chronic exercise alters the phenotype of coronary endothelial and vascular smooth muscle cells and that plasticity of these cells plays a role in adaptation of the cardiovascular system in exercise training.
The aims were: (1) to determine if a new ischaemia selective ATP dependent potassium (KATP) channel antagonist, sodium 5-hydroxydecanoate (5-HD), blocks ischaemic preconditioning in dogs; (2) to determine whether a small intracoronary dose of glibenclamide, a classical sulphonylurea KATP channel antagonist, could block ischaemic preconditioning independent of systemic metabolic effects.
Barbitone anaesthetised dogs were subjected to 60 min of left circumflex coronary artery occlusion followed by 5 h of reperfusion. Preconditioning was produced by a single 5 min left circumflex occlusion followed by 10 min of reperfusion prior to the 60 min occlusion period. 5-HD (150 micrograms.kg-1 x min-1) or vehicle was given by intracoronary infusion into the ischaemic region over 20 min, beginning 15 min prior to the 60 min occlusion period in the presence or absence of preconditioning. Glibenclamide (3 micrograms.kg-1 x min-1) was given by intracoronary infusion into the left circumflex artery during the 5 min preconditioning period or during the first 5 min of occlusion in preconditioned or non-preconditioned dogs. Transmural myocardial blood flow was measured by radioactive microspheres and infarct size determined by triphenyltetrazolium staining and expressed as a percent of the area at risk.
There were no differences in haemodynamic variables, myocardial blood flow, area at risk, or blood glucose between groups. Infarct size was markedly reduced in preconditioned dogs compared to control animals, at 7(SEM 2)% v 29(4)%, p < 0.05 The reduction in infarct size by preconditioning was blocked completely by intracoronary 5-HD, or by intracoronary glibenclamide given during preconditioning or during the first 5 min of the prolonged occlusion period. Neither 5-HD nor glibenclamide affected infarct size in the absence of preconditioning at the doses studied.
These results further strengthen the hypothesis that activation of myocardial KATP channels is involved in the mechanism of ischaemic preconditioning in dogs.
Single or multiple brief periods of ischemia (preconditioning) have been shown to protect the myocardium from infarction after a subsequent more prolonged ischemic insult. To test the hypothesis that preconditioning is the result of opening ATP-sensitive potassium (KATP) channels, a selective KATP channel antagonist, glibenclamide, was administered before or immediately after preconditioning in barbital-anesthetized open-chest dogs subjected to 60 minutes of left circumflex coronary artery (LCX) occlusion followed by 5 hours of reperfusion. Preconditioning was elicited by 5 minutes of LCX occlusion followed by 10 minutes of reperfusion before the 60-minute occlusion period. Glibenclamide (0.3 mg/kg i.v.) or vehicle was given 10 minutes before the initial ischemic insult in each of four groups. In a fifth group, glibenclamide was administered immediately after preconditioning. In a final series (group 6), a selective potassium channel opener, RP 52891 (10 micrograms/kg bolus and 0.1 micrograms/mg/min i.v.) was started 10 minutes before occlusion and continued throughout reperfusion. Transmural myocardial blood flow was measured at 30 minutes of occlusion, and infarct size was determined by triphenyltetrazolium staining and expressed as a percent of the area at risk. There were no significant differences in hemodynamics, collateral blood flow, or area at risk between groups. The ratio of infarct size to area at risk in the control group (28 +/- 6%) was not different from the group pretreated with glibenclamide in the absence of preconditioning (31 +/- 6%). Preconditioning produced a marked reduction (p less than 0.002) in infarct size (28 +/- 6% to 6 +/- 2%), whereas glibenclamide administered before or immediately after preconditioning completely abolished the protective effect (28 +/- 6% and 30 +/- 8%, respectively). RP 52891 also produced a significant (p less than 0.03) reduction (28 +/- 6% to 13 +/- 3%) in infarct size. These results suggest that myocardial preconditioning in the canine heart is mediated by activation of KATP channels and that these channels may serve an endogenous myocardial protective role.
Mitochondria take up and extrude various inorganic and organic ions, as well as larger substances such as proteins. The technique of patch clamping should provide real-time information on such transport and on energy transduction in oxidative phosphorylation. It has been applied to detect microscopic currents from mitochondrial membranes and conductances of ion channels in the 5-1,000 pS range in the outer and inner membranes. These pores are not, however, selective for particular ions. Here we use fused giant mitoplasts prepared from rat liver mitochondria to identify a small conductance channel highly selective for K+ in the inner mitochondrial membrane. This channel can be reversibly inactivated by ATP applied to the matrix side under inside-out patch configuration; it is also inhibited by 4-aminopyridine and by glybenclamide. The slope conductance of the unitary currents measured at negative membrane potentials was 9.7 +/- 1.0 pS (mean +/- s.d., n = 6) when the pipette solution contained 100 mM K+ and the bathing solution 33.3 mM K+. Our results indicate that mitochondria depolarize by generating a K+ conductance when ATP in the matrix is deficient.
Both acute acetaminophen toxicity and physical exercise are accompanied by structural and functional damage to tissues. For acute acetaminophen toxicity, this damage occurs mainly in the liver. This damage, which is believed to be initially caused by oxidation and/or arylation, occurs only after depletion of liver glutathione (GSH). GSH normally protects against oxidation and/or arylation. Prolonged physical exercise also depletes GSH in the body. We hypothesized that with endurance training (repeated oxidant stress) tissues will develop mechanisms to prevent GSH depletion. Our results show that, for the same amount of submaximal exercise, trained rats are able to maintain their levels of GSH or their GSH redox status (in the liver, heart, skeletal muscle and plasma) in contrast to their untrained counterparts. Also, upon administration of acetaminophen, trained rats show a less pronounced depletion in liver GSH than untrained rats. We also hypothesized that training may lead to improved maintenance of tissue GSH homeostasis because of induction in the enzyme pathways of protection. We observe that training significantly increases (50-70%) glutathione peroxidase and reductase, glucose-6-phosphate dehydrogenase, and catalase activity in heart and skeletal muscle. Since GSH, in addition to providing cellular protection, also functions in other physiological processes including transport and metabolism, the training-induced benefits seen here may have more far-reaching consequences than ever before realized.
The purpose of this study was to correlate the exercise-induced changes of oxidant stress enzymes with possible modification of the response to the putative oxidant stressor doxorubicin. Enzymatic and histological changes were studied in mice placed on a 21-wk swim training program (1 h/day, 5 days/wk) with and without anthracycline administration. Doxorubicin (4 mg/kg) was administered intravenously through a tail vein on 10 separate days over a 7-wk period (twice weekly during weeks 10, 11, 14, 15, and 16). Blood, liver, and heart levels of catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GP) were measured following the 9th and 21st wk. Myocardial histomorphological observations were made by light microscopy after 21 wk. Following 9 wk of training swim-trained animals had significantly elevated levels of CAT, SOD, and GP in blood, as well as elevated GP in liver. After 21 wk, trained animals, regardless of drug status, had elevated blood CAT and SOD activity and increased liver CAT and GP. Training also produced increases in blood GP, liver SOD, and heart CAT; however, in conjunction with doxorubicin these changes were not seen. The degree of cardiotoxicity was significantly greater in the sedentary drug-treated animals than in the swim-trained drug-treated animals. The results suggest a correlation between antioxidant enzyme levels in blood and liver and the degree of damage caused by an anthracycline drug. It was concluded that exercise ameliorates severe toxic damage caused by doxorubicin administration, possibly by increasing enzymes that combat free radical damage.
An outward current of unknown nature increases significantly when cardiac cells are treated with cyanide or subjected to hypoxia, and decreases on intracellular injection of ATP. We report here that application of the patch-clamp technique to CN-treated mammalian heart cells reveals specific K+ channels which are depressed by intracellular ATP (ATPi) at levels greater than 1 mM. For these channels, conductance in the outward direction is much larger than the inward rectifier K+ channel which is insensitive to ATP. AMP had no effect on the ATP-sensitive K+ channel, and ADP was less effective than ATP. Thus, the ATP-sensitive K+ channel seems to be important for regulation of cellular energy metabolism in the control of membrane excitability.
The effects of acute and trained exercise on antioxidant enzymes (AOE), glutathione (GSH), and malondialdehyde (MDA) were compared in rat heart subcellular fractions and red blood cells. Fischer-344 rats were exercised acutely to 100% VO2 max and another group of Fischer-344 rats were given trained exercise for 10 weeks. The AOE and MDA were measured by spectrophotometry and GSH and oxidized GSH (GSSG) by high pressure liquid chromatography. Trained exercise significantly increased cytosol GSH to 131% of sedentary control (SC). Acute exercise significantly increased mitochondrial superoxide dismutase, catalase, and glutathione peroxidase by 167%, 358%, and 129% of SC, respectively, whereas enzyme activities following trained exercise were increased by 133%, 166%, and 128% of SC. The mitochondria/cytosolic ratio for superoxide dismutase, catalase, and glutathione peroxidase after acute exercise increased to 1.9, 2.7, and 1.7, respectively, whereas the respective ratios of these enzymes after trained exercise were 1.3, 1.6, and 1.3. Acute exercise contributed to oxidative stress more than trained exercise. Acute exercise resulted in a larger increase in enzyme activities than trained exercise, possibly as a compensatory mechanism to cope with the enhanced production of superoxides and oxyradicals during exhaustive exercise.
Hearts from treadmill-trained and sedentary rats were perfused in the working heart mode. Mechanical and metabolite status was evaluated before ischemia, after 25 min of global ischemia, and after 30 min of retrograde reperfusion. After reperfusion, hearts from trained rats were found to have better recovery of contractile function, lower diastolic stiffness, greater efficiency of work, and greater extracellular calcium responsiveness than hearts from sedentary rats. Training had no significant impact on bioenergetic status before or at the end of ischemia. However, after reperfusion, both phosphocreatine and ATP were significantly higher in hearts from trained rats than from sedentary control rats. Mitochondrial function in both subsarcolemmal and intermyofibrillar subpopulations was unaffected by ischemia-reperfusion. 45Ca2+ uptake during reperfusion was significantly higher in hearts from sedentary rats than from exercise-trained rats. No differences were found in free radical production or tolerance due to training. Therefore, hearts from exercise-trained rats demonstrated an increased metabolic tolerance to ischemic-reperfusion damage, which may contribute to the improved postischemic functional recovery.
Previous studies have demonstrated that induction of heat shock protein (HSP) 72 by whole-body hyperthermia reduces infarct size in an in vivo model of ischemia and reperfusion. Furthermore, hearts obtained from transgenic mice that overexpress HSP72 demonstrate improved functional recovery and decreased infarct size in vitro after global ischemia and reperfusion.
To test the hypothesis that overexpression of HSP72 in transgenic mice reduces infarct size in vivo, transgenic mice that were heterozygous for a rat HSP70i gene ([+]HSP72) and transgene-negative littermate controls ([-]HSP72) were subjected to 30 minutes of left coronary artery occlusion followed by 120 minutes of reperfusion. Core body temperature was monitored with a rectal thermometer and maintained between 36.5 degrees C and 37.0 degrees C with a heating pad. Infarct size, determined by dual staining with triphenyltetrazolium chloride and phthalocyanine blue dye, was smaller in [+]HSP72 mice compared with [-]HSP72 mice (12.7 +/- 2.8% [n = 7] versus 33.4 +/- 4.5% [n = 6], infarct size/risk area, respectively; P < .05; mean +/- SEM).
Overexpression of HSP72 reduces infarct size in this in vivo transgenic mouse model of myocardial ischemia and reperfusion.
Previous studies showed a poor correlation between sarcolemmal K+ currents and cardioprotection for ATP-sensitive K+ channel (KATP) openers. Diazoxide is a weak cardiac sarcolemmal KATP opener, but it is a potent opener of mitochondrial KATP, making it a useful tool for determining the importance of this mitochondrial site. In reconstituted bovine heart KATP, diazoxide opened mitochondrial KATP with a K1/2 of 0.8 mumol/L while being 1000-fold less potent at opening sarcolemmal KATP. To compare cardioprotective potency, diazoxide or cromakalim was given to isolated rat hearts subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. Diazoxide and cromakalim increased the time to onset of contracture with a similar potency (EC25, 11.0 and 8.8 mumol/L, respectively) and improved postischemic functional recovery in a glibenclamide (glyburide)-reversible manner. In addition, sodium 5-hydroxydecanoic acid completely abolished the protective effect of diazoxide. While-myocyte studies showed that diazoxide was significantly less potent than cromakalim in increasing sarcolemmal K+ currents. Diazoxide shortened ischemic action potential duration significantly less than cromakalim at equicardioprotective concentrations. We also determined the effects of cromakalim and diazoxide on reconstituted rat mitochondrial cardiac KATP activity. Cromakalim and diazoxide were both potent activators of K+ flux in this preparation (K1/2 values, 1.1 +/- 0.1 and 0.49 +/- 0.05 mumol/L, respectively). Both glibenclamide and sodium 5-hydroxydecanoic acid inhibited K+ flux through the diazoxide-opened mitochondrial KATP. The profile of activity of diazoxide (and perhaps KATP openers in general) suggests that they protect ischemic hearts in a manner that is consistent with an interaction with mitochondrial KATP.
How a cell responds to stress is a central problem in cardiovascular biology. Diverse physiological stresses (eg, heat, hemodynamics, mutant proteins, and oxidative injury) produce multiple changes in a cell that ultimately affect protein structures and function. Cells from different phyla initiate a cascade of events that engage essential proteins, the molecular chaperones, in decisions to repair or degrade damaged proteins as a defense strategy to ensure survival. Accumulative evidence indicates that molecular chaperones such as the heat shock family of stress proteins (HSPs) actively participate in an array of cellular processes, including cytoprotection. The versatility of the ubiquitous HSP family is further enhanced by stress-inducible regulatory networks, both at the transcriptional and posttranscriptional levels. In the present review, we discuss the regulation and function of HSP chaperones and their clinical significance in conditions such as cardiac hypertrophy, vascular wall injury, cardiac surgery, ischemic preconditioning, aging, and, conceivably, mutations in genes encoding contractile proteins and ion channels.
The use of electrophysiological and molecular biology techniques has shed light on reactive oxygen species (ROS)-induced impairment of surface and internal membranes that control cellular signaling. These deleterious effects of ROS are due to their interaction with various ion transport proteins underlying the transmembrane signal transduction, namely, 1) ion channels, such as Ca2+ channels (including voltage-sensitive L-type Ca2+ currents, dihydropyridine receptor voltage sensors, ryanodine receptor Ca2+-release channels, and D-myo-inositol 1,4,5-trisphosphate receptor Ca2+-release channels), K+ channels (such as Ca2+-activated K+ channels, inward and outward K+ currents, and ATP-sensitive K+ channels), Na+ channels, and Cl- channels; 2) ion pumps, such as sarcoplasmic reticulum and sarcolemmal Ca2+ pumps, Na+-K+-ATPase (Na+ pump), and H+-ATPase (H+ pump); 3) ion exchangers such as the Na+/Ca2+ exchanger and Na+/H+ exchanger; and 4) ion cotransporters such as K+-Cl-, Na+-K+-Cl-, and Pi-Na+ cotransporters. The mechanism of ROS-induced modifications in ion transport pathways involves 1) oxidation of sulfhydryl groups located on the ion transport proteins, 2) peroxidation of membrane phospholipids, and 3) inhibition of membrane-bound regulatory enzymes and modification of the oxidative phosphorylation and ATP levels. Alterations in the ion transport mechanisms lead to changes in a second messenger system, primarily Ca2+ homeostasis, which further augment the abnormal electrical activity and distortion of signal transduction, causing cell dysfunction, which underlies pathological conditions.
The purpose of these experiments was to test the hypothesis that endurance exercise training will reduce myocardial lipid peroxidation following short-term ischemia and reperfusion (I-R).
Female Sprague-Dawley rats (4 months old) were randomly assigned to either a sedentary control group (N = 13) or to an exercise training group (N = 13). The exercise trained animals ran 4 d.wk-1 (90 min.d-1) at approximately 75% V02max. Following a 10-wk training program, animals were anesthetized, mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 5 min followed by a 10-min period of reperfusion.
Although training did not alter (P > 0.05) myocardial activities of antioxidant enzymes (superoxide dismutase and glutathione peroxidase), training was associated with significant increase (P > 0.05) in heat shock protein (HSP72) in the left ventricle. Compared with controls, trained animals exhibited significantly lower levels (P < 0.05) of myocardial lipid peroxidation following I-R.
These data support the hypothesis that exercise training provides protection against myocardial lipid peroxidation induced by short-term I-R in vivo.
The sarcoplasmic reticulum (SR) calcium ATPase carries out active Ca2+ pumping at the expense of ATP hydrolysis. We have previously described the inhibition of SR ATPase by oxidative stress induced by the Fenton reaction (Fe2+ + H2O2 --> HO. + HO- + Fe3+). Inhibition was not related to peroxidation of the SR membrane nor to oxidation of ATPase thiols, and involved fragmentation of the ATPase polypeptide chain. The present study aims at further characterizing the mechanism of inhibition of the Ca2+-ATPase by oxygen reactive species at Fe2+ concentrations possibly found in pathological conditions of iron overload. ATP hydrolysis by SR vesicles was inhibited in a dose-dependent manner by micromolar concentrations of Fe2+, H2O2, and ascorbate. Measuring the rate constants of inactivation (k inact) at different Fe2+ concentrations in the presence of saturating concentrations of H2O2 and ascorbate (100 microM each) revealed a saturation profile with half-maximal inactivation rate at ca. 2 microM Fe2+. Inhibition was not affected by addition of 200 microM Ca2+ to the medium, indicating that it was not related to iron binding to the high affinity Ca2+ binding sites in the ATPase. Furthermore, inhibition was not prevented by the water-soluble hydroxyl radical scavengers mannitol or dimethylsulfoxide, nor by butylated hydroxytoluene (a lipid peroxidation blocker) or dithiothreitol (DTT). However, when Cu2+ was used instead of Fe2+ in the Fenton reaction, ATPase inhibition could be prevented by DTT. We propose that functional impairment of the Ca2+-pump may be related to oxidative protein fragmentation mediated by site-specific Fe2+ binding at submicromolar or low micromolar concentrations, which may occur in pathological conditions of iron overload.
Generation of free radicals upon reperfusion has been cited as one of the major causes of ischaemia/reperfusion injury. The following series of experiments was designed to study the effect of manganese superoxide dismutase (MnSOD) overexpression in transgenic mice on ischemia/reperfusion injury. A species of 1.4 kb human MnSOD mRNA was expressed, and a 325% increase in MnSOD activity was detected in the hearts of transgenic mice with no changes in the other antioxidant enzymes or heat shock proteins. Immunocytochemical study indicated an increased labeling of MnSOD mainly in the heart mitochondria of the transgenic mice. When these hearts were perfused as Langendorff preparations for 45 min after 35 min of global ischemia, the functional recovery of the hearts, expressed as heart rate x left ventricular developed pressure, was 52 +/- 4% in the transgenic hearts as compared to 31 +/- 4% in the non-transgenic hearts. This protection was accompanied by a significant decrease in lactate dehydrogenase release from the transgenic hearts. Overexpression of MnSOD limited the infarct size in vivo in a left coronary artery ligation model. Our results demonstrate that overexpression of MnSOD renders the heart more resistant to ischemia/reperfusion injury.
The aim of this study was to determine the effects of acute bouts of exercise on myocardial recovery after ischemia and heat shock protein expression. Adult female Sprague-Dawley rats were divided into five groups: 1) 1-day run (1DR; n = 6) and 2) 3-day run (3DR; n = 7), in which rats ran for 100 min at a speed of 20 m/min up a 6 degrees grade for 1 or 3 consecutive days; 3) 1-day cold run (1CR), in which rats ran the same as 1DR but with wet fur at 8 degrees C, which prevented an elevation of core temperature (n = 8); 4) heat shock sedentary (HS), in which rats had their core temperatures raised to 42 degrees C one time for 15 min (n = 5); and 5) sedentary control (n=15). Cardiac function was analyzed 24 h after the last treatment using an isolated, working heart model. Nonpaced hearts were initially perfused under normoxic conditions, then underwent 17 min of global, normothermic (37 degrees C) ischemia, and, finally, were allowed to recover for 30 min under normoxic conditions. The concentration of the 72-kDa heat shock protein (HSP 72) was measured in each left ventricle. Compared with that in the sedentary group, recovery of cardiac output x systolic pressure (CO x SP) was enhanced (P < 0.05) in all treatment groups when the postischemic value was covaried with the preischemic value. No differences in CO x SP were found (P > 0.05) between the following groups: 1DR vs. 3DR, 1DR vs. HS, and 1DR vs. 1CR. Heat shock protein concentration was significantly greater (P < 0.05) than that in the sedentary controls in HS, 1DR, and 3DR groups, but not for 1CR. The concentration of HSP 72 was not significantly correlated with postischemic CO x SP (R2 = 0.197, P > 0.05). We conclude that acute bouts of exercise can produce cardioprotective effects without an elevation of HSP 72.
The past two decades have witnessed an explosive growth of knowledge regarding postischemic myocardial dysfunction or myocardial "stunning." The purpose of this review is to summarize current information regarding the pathophysiology and pathogenesis of this phenomenon. Myocardial stunning should not be regarded as a single entity but rather as a "syndrome" that has been observed in a wide variety of experimental settings, which include the following: 1) stunning after a single, completely reversible episode of regional ischemia in vivo; 2) stunning after multiple, completely reversible episodes of regional ischemia in vivo; 3) stunning after a partly reversible episode of regional ischemia in vivo (subendocardial infarction); 4) stunning after global ischemia in vitro; 5) stunning after global ischemia in vivo; and 6) stunning after exercise-induced ischemia (high-flow ischemia). Whether these settings share a common mechanism is unknown. Although the pathogenesis of myocardial stunning has not been definitively established, the two major hypotheses are that it is caused by the generation of oxygen-derived free radicals (oxyradical hypothesis) and by a transient calcium overload (calcium hypothesis) on reperfusion. The final lesion responsible for the contractile depression appears to be a decreased responsiveness of contractile filaments to calcium. Recent evidence suggests that calcium overload may activate calpains, resulting in selective proteolysis of myofibrils; the time required for resynthesis of damaged proteins would explain in part the delayed recovery of function in stunned myocardium. The oxyradical and calcium hypotheses are not mutually exclusive and are likely to represent different facets of the same pathophysiological cascade. For example, increased free radical formation could cause cellular calcium overload, which would damage the contractile apparatus of the myocytes. Free radical generation could also directly alter contractile filaments in a manner that renders them less responsive to calcium (e.g., oxidation of critical thiol groups). However, it remains unknown whether oxyradicals play a role in all forms of stunning and whether the calcium hypothesis is applicable to stunning in vivo. Nevertheless, it is clear that the lesion responsible for myocardial stunning occurs, at least in part, after reperfusion so that this contractile dysfunction can be viewed, in part, as a form of "reperfusion injury." An important implication of the phenomenon of myocardial stunning is that so-called chronic hibernation may in fact be the result of repetitive episodes of stunning, which have a cumulative effect and cause protracted postischemic dysfunction. A better understanding of myocardial stunning will expand our knowledge of the pathophysiology of myocardial ischemia and provide a rationale for developing new therapeutic strategies designed to prevent postischemic dysfunction in patients.
Left ventricular (LV) diastolic function is an important determinant of aerobic fitness. The purpose of this paper was to investigate the relationship between aerobic fitness and the rate and extent of isovolumic LV relaxation.
Two series of experiments were performed utilizing both human and animal models. In the first series of experiments, the relationship between LV diastolic time intervals and exercise capacity was assessed in two groups of collegiate men (N = 18) with variable peak run times (Bruce protocol). In the second series of experiments, the extent of LV relaxation was examined in sedentary and exercise-trained rats (treadmill running), using an isolated, isovolumic heart preparation. Subsequent morphological assessment was also performed in rats.
At rest, men with greater peak treadmill time had a shorter resting LV isovolumic relaxation time (R-R interval adjusted 1000 ms) (long duration runners, 84+/-5 ms vs short duration runners, 105+/-7 ms, P < 0.05) despite a similar LV diastolic interval. Peak treadmill time was inversely correlated to LV isovolumic relaxation time (R-R interval adjusted 1000 ms) (r = -0.55; P < 0.02). In animal studies (N = 26), the LV pressure-volume relationship was shifted rightward in exercise-trained rats (P = 0.003). Exercise-trained rats had an increased LV inner diameter (sedentary, 5.1+/-0.35 mm vs exercise-trained, 6.1+/-0.28 mm, P < 0.05) and a thicker interventricular septum (sedentary, 1.52+/-0.06 mm vs exercise-trained, 1.72+/-0.09 mm, P < 0.05).
This study suggests that both the rate and extent of LV isovolumic relaxation is enhanced with exercise training. Further study is required to understand the interrelationship between exercise and diastolic function.
Heat shock proteins (HSPs) play a critical role in maintaining cellular homeostasis and protecting cells during episodes of acute stress. Specifically, HSPs of the 70 kDa family (i.e., HSP72) are important in preventing ischemia-reperfusion induced apoptosis, necrosis, and oxidative injury in a variety of cell types including the cardiac myocyte. Evidence indicates that HSP72 may contribute to cellular protection against a variety of stresses by preventing protein aggregation, assisting in the refolding of damaged proteins, and chaperoning nascent polypeptides along ribosomes. Endurance exercise is a physiological stress that can be used to elevate myocardial levels of HSP72. It is now clear that endurance exercise training can elevate myocardial HSP72 by 400-500% in young adult animals. Importantly, an exercise-induced elevation in myocardial HSPs is associated with a reduction in ischemia-reperfusion (I-R) injury in the heart. Although it seems likely that exercise-induced elevations in myocardial levels of HSPs play an important role in this protection against an I-R insult, new evidence suggests that other factors may also be involved. This is an important area for future research.
We have previously demonstrated that K(ATP)channel openers administered just prior to and throughout reperfusion induce cardioprotection in the blood-perfused canine heart. However, a recent report suggests that the mitochondrial K(ATP)channel is only a trigger of ischemic preconditioning (IPC). These recent data are, however, in contrast to most previous investigations that suggested that activation of the mitochondrial K(ATP)channel is an important downstream mediator of cardioprotection. Therefore, we examined the role of the mitochondrial K(ATP)channel as a downstream mediator of IPC in a rat model by administering the selective mitochondrial K(ATP)channel antagonist, 5-hydroxydecanoate (5-HD), at several points during IPC. Infarct size (IS) was determined by tetrazolium chloride staining and expressed as a percent of the area at risk (AAR). Control animals had an IS/AAR of 58.4+/-0.6 and IS/AAR was reduced to 6.2+/-1.7 following IPC. 5-HD (10 mg/kg), attenuated cardioprotection when administered either 5 min prior to the IPC stimulus (40.4+/-1.4), during the reperfusion phase of the IPC stimulus (39.7+/-5.9), or 5 min prior to reperfusion during prolonged ischemia (34.3+/-6.9). Additionally, when 5-HD was administered at 5 mg/kg during the reperfusion phase of index ischemia plus 5 min prior to IPC or plus during the reperfusion phase of IPC, cardioprotection was also attenuated (36.3+/-5.5 and 43.8+/-6.9, respectively). These data suggest that activation of the mitochondrial K(ATP) channel is an important downstream regulator of myocardial protection with effects lasting into the reperfusion period following prolonged ischemia.
Alterations in the production of nitric oxide (NO.) are a critical factor in the injury that occurs in ischemic and reperfused myocardium; however, controversy remains regarding the alterations in NO. that occur and how these alterations cause tissue injury. As superoxide generation occurs during the early period of reperfusion, the cytotoxic oxidant peroxynitrite (ONOO-) could be formed; however, questions remain regarding ONOO- formation and its role in postischemic injury. Electron paramagnetic resonance spin trapping studies, using the NO. trap Fe(2+)-N-methyl-D-glucamine dithiocarbamate (Fe-MGD), and chemiluminescence studies, using the enhancer luminol, have been performed to measure the magnitude and time course of NO. and ONOO- formation in the normal and postischemic heart. Isolated rat hearts were subjected to control perfusion, or ischemia followed by reperfusion in the presence of Fe-MGD with electron paramagnetic resonance measurements performed on the effluent from these hearts. Whereas only trace signals were present prior to ischemia, prominent NO. adduct signals were seen during the first 2 min of reflow. The reperfusion associated increase in these NO. signals was abolished by nitric oxide synthase inhibition. In hearts perfused with luminol to detect ONOO- formation, a similar marked increase was seen during the first 2 min of reperfusion that was blocked by nitric oxide synthase inhibitors and by superoxide dismutase. Either NG-nitro-L-arginine methyl ester or superoxide dismutase treatment resulted in more than twofold higher recovery of contractile function than in untreated hearts. Immunohistology studies demonstrated that the ONOO(-)-mediated nitration product nitrotyrosine was formed in postischemic hearts, but not in normally perfused controls. Thus, NO. formation is increased during the early period of reperfusion and reacts with superoxide to form ONOO-, which results in protein nitration and myocardial injury.
This study determined the role of body temperature during chronic exercise on myocardial stress proteins and antioxidant enzymes as well as functional recovery after an ischemic insult. Male Sprague-Dawley rats were exercised for 3, 6, or 9 wk in a 23 degrees C room (3WK, 6WK, and 9WK, respectively) or in a 4-8 degrees C environment with wetted fur (3WKC, 6WKC, and 9WKC, respectively). The colder room prevented elevations in core temperature. During weeks 3-9 the animals ran 5 days/wk up a 6% grade at 20 m/min for 60 min. Myocardial heat shock protein 70 (HSP 70) increased 12.3-fold (P < 0.05) in 9WK versus sedentary (SED) rats but was unchanged in the cold-room runners. Compared with SED rats, alphaB-crystallin was 90% higher in 9WKC animals, HSP 90 was 50% higher in 3WKC and 6WKC animals, and catalase was 23% higher in 3WK animals (P < 0.05 for all). Cytosolic superoxide dismutase increased and mitochondrial SOD decreased (P < 0.05) in 3WK and 6WK rats compared with 3WKC and 6WKC rats. Antioxidant enzymes returned to SED values in all runners by 9 wk. No differences were observed among any of the groups for glucose-regulated protein 75, heme oxygenase-1, or glutathione peroxidase. Mechanical recovery of isolated working hearts after 22.5 min of global ischemia was enhanced in 9WK (P < 0.05) but not in 9WKC rats. We conclude that exercise training results in dynamic changes in cardioprotective proteins over time which are influenced by core temperature. In addition, cardioprotection resulting from chronic exercise appears to be due to increased HSP 70.
X. Kong, J. S. Tweddell, G. J. Gross and J. E. Baker. Sarcolemmal and Mitochondrial K(ATP)Channels Mediate Cardioprotection in Chronically Hypoxic Hearts. Journal of Molecular and Cellular Cardiology (2001) 33, 1041-1045. Hypoxia from birth increases the resistance of the isolated neonatal heart to ischemia. We determined if increased resistance to ischemia was due to activation of sarcolemmal or mitochondrial K(ATP)channels. Rabbits (n=8/group) were raised from birth in a normoxic (F(I)O(2)=0.21) or hypoxic (F(I)O(2)=0.12) environment for 8-10 days and the heart perfused with Krebs-Henseleit bicarbonate buffer. A mitochondrial-selective K(ATP)channel blocker 5-hydroxydecanoate (5-HD) (300 micromol/l) or a sarcolemmal-selective K(ATP)channel blocker HMR 1098 (30 micromol/l) were added alone or in combination for 20 min prior to a global ischemic period of 30 min, followed by 35 min reperfusion. Recovery of ventricular developed pressure was higher in chronically hypoxic than normoxic hearts. 5-HD and HMR 1098 partially reduced the cardioprotective effect of chronic hypoxia, but had no effect in normoxic hearts. The combination of 5-HD and HMR 1098 abolished the cardioprotective effect of chronic hypoxia. We conclude that both sarcolemmal and mitochondrial K(ATP)channels contribute to cardioprotection in the chronically hypoxic heart.
Upregulation of heat shock protein 70 (HSP70) is beneficial in cardioprotection against ischemia-reperfusion injury, but the mechanism of action is unclear. We studied the role of HSP70 overexpression through gene therapy on mitochondrial function and ventricular recovery in a protocol that mimics clinical donor heart preservation.
Hemagglutinating virus of Japan (HVJ)-liposome technique was used to transfect isolated rat hearts via intracoronary infusion of either the HSP70 gene (HSP group, n=16) or no gene (CON group, n=16), which was heterotopically transplanted into recipient rats. Four days after surgery, hearts were either perfused on a Langendorff apparatus for 30 minutes at 37 degrees C (preischemia studies [n=8/group]) or perfused for 30 minutes at 37 degrees C, cardioplegically arrested for 4 hours at 4 degrees C, and reperfused for 30 minutes at 37 degrees C (postischemia studies [n=8/group]). Western blotting and immunohistochemistry confirmed HSP70 upregulation in the HSP group. Postischemic mitochondrial respiratory control indices (RCIs) were significantly better preserved in HSP than in CON hearts: NAD(+)-linked RCI values were 9.54+/-1.1 versus 10.62+/-0.46 before ischemia (NS) but 7.98+/-0.69 versus 1.28+/-0.15 after ischemia (P<0.05), and FAD-linked RCI values were 6.87+/-0.88 versus 6.73+/-0.93 before ischemia (NS) but 4.26+/-0.41 versus 1.34+/-0.13 after ischemia (P<0.05). Postischemic recovery of mechanical function was greater in HSP than in CON hearts: left ventricular developed pressure recovery was 72.4+/-6.4% versus 59.7+/-5.3% (P<0.05), maximum dP/dt recovery was 77.9+/-6.6% versus 52.3+/-5.2% (P<0.05), and minimum dP/dt recovery was 72.4+/-7.2% versus 54.8+/-6.9% (P<0.05). Creatine kinase release in coronary effluent after reperfusion was 0.20+/-0.04 versus 0.34+/-0.06 IU. min(-1). g wet wt(-1) (P<0.05) in HSP versus in CON hearts.
HSP70 upregulation protects mitochondrial function after ischemia-reperfusion injury; this was associated with improved preservation of ventricular function. Protection of mitochondrial function may be important in the development of future cardioprotective strategies.
Exacerbation of hypoxic injury after restoration of oxygenation (reoxygenation) is an important mechanism of cellular injury in transplantation and in myocardial, hepatic, intestinal, cerebral, renal, and other ischemic syndromes. Cellular hypoxia and reoxygenation are two essential elements of ischemia-reperfusion injury. Activated neutrophils contribute to vascular reperfusion injury, yet posthypoxic cellular injury occurs in the absence of inflammatory cells through mechanisms involving reactive oxygen (ROS) or nitrogen species (RNS). Xanthine oxidase (XO) produces ROS in some reoxygenated cells, but other intracellular sources of ROS are abundant, and XO is not required for reoxygenation injury. Hypoxic or reoxygenated mitochondria may produce excess superoxide (O) and release H(2)O(2), a diffusible long-lived oxidant that can activate signaling pathways or react vicinally with proteins and lipid membranes. This review focuses on the specific roles of ROS and RNS in the cellular response to hypoxia and subsequent cytolytic injury during reoxygenation.
More than 10 years after its discovery, the function of cyclooxygenase-2 (COX-2) in the cardiovascular system remains largely an enigma. Many scholars have assumed that the allegedly detrimental effects of COX-2 in other systems (e.g. proinflammatory actions and tumorigenesis) signify a detrimental role of this protein in cardiovascular homeostasis as well. This view, however, is ill-founded. Recent studies have demonstrated that ischemic preconditioning (PC) upregulates the expression and activity of COX-2 in the heart, and that this increase in COX-2 activity mediates the protective effects of the late phase of PC against both myocardial stunning and myocardial infarction. An obligatory role of COX-2 has been observed in the setting of late PC induced not only by ischemia but also by delta-opioid agonists and physical exercise, supporting the view that the recruitment of this protein is a central mechanism whereby the heart protects itself from ischemia. The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE(2) and/or PGI(2). Since inhibition of iNOS in preconditioned myocardium blocks COX-2 activity whereas inhibition of COX-2 does not affect iNOS activity, COX-2 appears to be downstream of iNOS in the protective pathway of late PC. The results of these studies challenge the widely accepted paradigm that views COX-2 activity as detrimental. The discovery that COX-2 plays an indispensable role in the anti-stunning and anti-infarct effects of late PC demonstrates that the recruitment of this protein is a fundamental mechanism whereby the heart adapts to stress, thereby revealing a novel, hitherto unappreciated cardioprotective function of COX-2. From a practical standpoint, the recognition that COX-2 is an obligatory co-mediator (together with iNOS) of the protection afforded by late PC has implications for the clinical use of COX-2 selective inhibitors as well as nonselective COX inhibitors. For example, the possibility that inhibition of COX-2 activity may augment myocardial cell death by obliterating the innate defensive response of the heart against ischemia/reperfusion injury needs to be considered and is the object of much current debate. Furthermore, the concept that the COX-2 byproducts, PGE(2) and/or PGI(2), play a necessary role in late PC provides a basis for novel therapeutic strategies designed to enhance the biosynthesis of these cytoprotective prostanoids in the ischemic myocardium. From a conceptual standpoint, the COX-2 hypothesis of late PC expands our understanding of the function of this enzyme in the cardiovascular system and impels a critical reassessment of current thinking regarding the biologic significance of COX-2.