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Exercise Increases Cystathionine-γ-lyase Expression and Decreases the Status of Oxidative Stress in Myocardium of Ovariectomized Rats

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Abstract

Exercise could be a therapeutic approach for cardiovascular dysfunction induced by estrogen deficiency. Our previous study has shown that estrogen maintains cystathionine-γ-lyase (CSE) expression and inhibits oxidative stress in the myocardium of female rats. In the present study, we investigated whether exercise improves CSE expression and oxidative stress status and ameliorates isoproterenol (ISO)-induced cardiac damage in ovariectomized (OVX) rats. The results showed that treadmill training restored the ovariectomy-induced reduction of CSE and estrogen receptor (ER)α and decrease of total antioxidant capacity (T-AOC) and increase of malondialdehyde (MDA). The level of CSE was positively correlated to T-AOC and ERα while inversely correlated to MDA. OVX rats showed increases in the serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) and the percentage of TUNEL staining in myocardium upon ISO insult compared to sham rats. Exercise training significantly reduced the serum levels of LDH and CK and the percentage of TUNEL staining in myocardium upon ISO insult in OVX rats. In cultured cardiomyocytes, ISO treatment decreased cell viability and increased LDH release, while overexpression of CSE increased cell viability and decreased LDH release in the cells upon ISO insult. The results suggest that exercise training improves the oxidative stress status and ameliorates the cardiac damage induced by oxidative stress in OVX rats. The improvement of oxidative stress status by exercise might be at least partially due to upregulation of CSE/H2S signaling.

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... Very intense or exhaustive exercise (either acute or prolonged) increases oxidation and downregulates the antioxidant defense resulting in excessive damage to macromolecules [61,62], whereas low-to-moderate intensity exercise (particularly repeated exercise bouts) enhances the activity of antioxidant enzymes and consequently lowers the levels of generated ROS and improves the cellular adaptation to subsequent stress [63,64]. For instance, a significant decrease in SOD, GPx, and catalase activity has been reported following exhaustive high intensity exercise [61,62], while an 8-week training program of moderate intensity resulted in improved total antioxidant capacity and reduce lipid oxidation [65]. ...
... Indeed, there has been documented that regular exercise increases the expression of major antioxidant enzymes and reduces that of pro-oxidant ones [70]. A recent study has shown that 8 weeks of cardiovascular exercise (CVE) training, enhanced the total antioxidant capacity (TAC) and reduced MDA levels in myocardium while it also ameliorated the cardiac damage induced by oxidative stress in ovariectomized rats [65]. The improved oxidative stress status induced by exercise was associated with cystathionine-γ-lyase expression (CSE) in myocardium, suggesting that this improvement might be at least partially due to the upregulation of CSE expression [65]. ...
... A recent study has shown that 8 weeks of cardiovascular exercise (CVE) training, enhanced the total antioxidant capacity (TAC) and reduced MDA levels in myocardium while it also ameliorated the cardiac damage induced by oxidative stress in ovariectomized rats [65]. The improved oxidative stress status induced by exercise was associated with cystathionine-γ-lyase expression (CSE) in myocardium, suggesting that this improvement might be at least partially due to the upregulation of CSE expression [65]. ...
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Although low levels of reactive oxygen species (ROS) are beneficial for the organism ensuring normal cell and vascular function, the overproduction of ROS and increased oxidative stress levels play a significant role in the onset and progression of cardiovascular diseases (CVDs). This paper aims at providing a thorough review of the available literature investigating the effects of acute and chronic exercise training and detraining on redox regulation, in the context of CVDs. An acute bout of either cardiovascular or resistance exercise training induces a transient oxidative stress and inflammatory response accompanied by reduced antioxidant capacity and enhanced oxidative damage. There is evidence showing that these responses to exercise are proportional to exercise intensity and inversely related to an individual’s physical conditioning status. However, when chronically performed, both types of exercise amplify the antioxidant defense mechanism, reduce oxidative stress and preserve redox status. On the other hand, detraining results in maladaptations within a time-frame that depends on the exercise training intensity and mode, as high-intensity training is superior to low-intensity and resistance training is superior to cardiovascular training in preserving exercise-induced adaptations during detraining periods. Collectively, these findings suggest that exercise training, either cardiovascular or resistance or even a combination of them, is a promising, safe and efficient tool in the prevention and treatment of CVDs.
... Antioxidant defence system prevents molecular and cellular damage by reducing free radicals (Halliwell, 2007;Gunay et al., 2011;Morrone et al.,2015). The evaluate of antioxidant enzyme activities are useful indicator of the antioxidant status in most mammals (Serin et al., 2008;Halliwell, 2012;Kozlik et al., 2015;Tang et al., 2016). Many studies on the evaluation of oxidative/antioxidative status in women and female rodents after ovariectomy or OHE have been demonstrated (Kankofer et al., 2007;Serin et al., 2008;Gunay et al., 2011;Szczubial et al., 2015). ...
... It has been known that postmenopausal life affects oxidative status and causes metabolic diseases like osteoporosis and cardiovascular disorders (Gurdol et al., 1997;Kankofer et al., 2007;Castelao et al., 2008;Yang et al., 2014;Tang et al., 2016). Similarly, ovariectomy in rats has long-term effects on several organs such as liver, intestines and myocardium due to deficiency of ovarian hormones, particularly estrogens following the surgery (Morrone et al., 2015;Tang et al., 2016;Barp et al., 2012;Gomez et al., 2012;Murphy, 2011). ...
... It has been known that postmenopausal life affects oxidative status and causes metabolic diseases like osteoporosis and cardiovascular disorders (Gurdol et al., 1997;Kankofer et al., 2007;Castelao et al., 2008;Yang et al., 2014;Tang et al., 2016). Similarly, ovariectomy in rats has long-term effects on several organs such as liver, intestines and myocardium due to deficiency of ovarian hormones, particularly estrogens following the surgery (Morrone et al., 2015;Tang et al., 2016;Barp et al., 2012;Gomez et al., 2012;Murphy, 2011). Estrogens have been demonstrated to protect the liver and intestines from oxidative damage due to its antioxidative properties (Sener et al., 2005). ...
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The purpose of the present study was to evaluate the effect of ovariohysterectomy (OHE) on oxidative stress in rats. A total of 12 female Sprague Dawley rats weighing 200-250 g were included in the study. Six rats underwent OHE (group I) and the other 6 rats sham operation (group II) under xylazine (5 mg/kg, i.m.) and ketamine (45 mg/kg, i.m.) anesthesia. In both groups, blood samples were collected preoperatively, day 1 and 10 th days after OHE. Serum concentration of malondialdehyde (MDA) and activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx) were measured by spectrophotometric methods. The concentration of MDA increased while activities of SOD and GPx decreased in group I compared to group II on day 1 after the surgery. Similarly, the concentration of MDA was higher while activities of SOD and GPx appeared to be lower in group I than that of group II, although the differences were not statistically significant on the 10 th day after surgery. In conclusion, our findings indicated that ovariohysterectomy is related with oxidative stress in the rat.
... Although not statistically significant, the LDL-C levels of rats given vitamin D, omega3 and exercised decreased compared to those in menopause [14,15,20,34]. Similarly, Tang et al. [35] reported that exercise significantly reduced LDL-C levels and ameliorating cardiac damage caused by oxidative stress in OVX rats. ...
... These data is a desired positive result [7,8,20,37]. In addition, Tang et al. [35], also found out that exercise improved OS status in OVX rats. Cappellari et al. [31], Zanetti et al. [32] and Marinho et al. [33] also reported positive effects of FO on OS in OVX rats. ...
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Objectives This study compared effects of vitamin D, fish oil and exercise on cardiovascular parameters in ovariectomized rats. Materials and methods This is an experimental study conducted with 45 female Wistar Albino rats; consisted of one sham (n=8) and four intervention (n=37) groups. Rats (n=37) were oophorectomized and, randomly divided into four groups at the end of the first week following wound healing. Interventions were applied to the groups of oophorectomize+Dvit, oophorectomize+fish oil and oophorectomize+exercise for 12 weeks. In analyzing the data, ANOVA and Tamhane’s T2 tests were used (p<0.05). Results The levels of total-cholesterol (66.7 ± 7.6 mg/dL), HDL-cholesterol (33.8 ± 2.1 mg/dL), TOS (7.3 ± 1.2 μmol H2O2 Eq/L), TAS (4.0 ± 0.5 mmol Trolox Eq/L), OSI (0.2 ± 0.1) and total-cholesterol/HDL-cholesterol (2.0 ± 0.3) were obtained significant in exercising oophorectomized rats according to the oophorectomized rats (p<0.05). The estrogen levels of rats using vitamin D and fish oil and exercising were found to be higher than those in menopause. Conclusions It was concluded that exercising oophorectomized rats had a lower risk of cardiovascular disease. In this context, exercise/physical activity should be recommended and must be supported for practicing in order to protect the cardiovascular health of postmenopausal women.
... However, when there is an overwhelming ROS production, it can disturb the cellular function and result in cell damage [3,4]. There are several studies that indicate that regular exercise can up-regulate the expression of major antioxidant enzymes and reduce the prooxidant molecules [74,75]. Furthermore, the exercise-mediated generation of free radicals seems to be essential for the activation of cellular transduction pathways that will promote beneficial adaptations leading to an antiatherogenic effect [9]. ...
... Most of the variables assessed were positively affected after training with CVT showing the most significant time-dependent changes. Results from research involving animals and humans are similar with the ones of this study, which have shown that CVT training improve antioxidant capacity [25,74,[76][77][78]. Healthy older individuals that exercised for 24 weeks with a moderate intensity for 3 days per week showed lower lipid peroxidation and inflammation and higher total antioxidant activity [25]. ...
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It is well-documented that chronic/regular exercise improves the cardiovascular function, decreases oxidative stress and enhances the antioxidant capacity in coronary artery disease (CAD) patients. However, there is insufficient evidence regarding the chronic effects of different types of training and detraining on cardiovascular function and the levels of oxidative stress and antioxidant status in these patients. Therefore, the present study aimed at investigating the effects of cardiovascular, resistance and combined exercise training followed by a three-month detraining period, on cardiovascular function, physical performance and blood redox status parameters in CAD patients. Sixty coronary artery disease patients were randomly assigned to either a cardiovascular training (CVT, N = 15), resistance training (RT, N = 11), combined cardiovascular and resistance training (CT, N = 16) or a control (C, N = 15) group. The training groups participated in an 8-month supervised training program (training three days/week) followed by a 3-month detraining period, while the control group participated only in measurements. Body composition, blood pressure, performance-related variables (aerobic capacity (VO2max), muscle strength, flexibility) and blood redox status-related parameters (thiobarbituric acid reactive substances (TBARS), total antioxidant capacity (TAC), reduced glutathione (GSH), oxidized glutathione (GSSG), catalase activity (CAT), protein carbonyls (PC)) were assessed at the beginning of the study, after 4 and 8 months of training as well as following 1, 2 and 3 months of detraining (DT). CVT induced the most remarkable and pronounced alterations in blood pressure (~9% reduction in systolic blood pressure and ~5% in diastolic blood pressure) and redox status since it had a positive effect on all redox-related variables (ranging from 16 to 137%). RT and CT training affected positively some of the assessed (TAC, CAT and PC) redox-related variables. Performance-related variables retained the positive response of the training, whereas most of the redox status parameters, for all training groups, restored near to the pre-exercise values at the end of the DT period. These results indicate that exercise training has a significant effect on redox status of CAD. Three months of detraining is enough to abolish the exercise-induced beneficial effects on redox status, indicating that for a better antioxidant status, exercise must be a lifetime commitment.
... As a non-pharmacological therapeutic approach, exercise was demonstrated to have beneficial effects in attenuating cardiometabolic syndrome, improving antioxidant status, reducing proinflammatory cytokine levels, and ameliorating cardiovascular dysfunction in OVX rats [60][61][62][63][64]. Clinical studies verified the advantageous effects of exercise training on metabolic and lipid profiles and cardiorespiratory fitness of postmenopausal women [16,65,66]. ...
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We aimed to evaluate the impact of hormone replacement, melatonin, or exercise alone or their combination on oxidative damage and functional status of heart, brain, and aorta of ovariectomized (OVX) rats and to determine whether the signaling pathway is dependent on sirtuin-1 (SIRT1). Ovariectomized Sprague Dawley rats were orally given either a hormone replacement therapy (1 mg/kg/day,17β estradiol; HRT) or melatonin (4 mg/kg/day) or HRT + melatonin treatments or tap water, while each group was further divided into sedentary and exercise (30 min/5 days/week) groups. After the heart rate measurements and memory tests were performed, trunk blood was collected at the end of the 10th week to determine metabolic parameters in serum samples. Tissue samples of abdominal aorta, heart, and brain were taken for biochemical measurements and histopathological evaluation. Heart rates and memory performances of the OVX rats were not changed significantly by none of the applications. Melatonin treatment or its co-administration with HRT upregulated the expressions of IL-10 and SIRT1, reduced the expressions of IL-6 and TNF-α, and reduced DNA damage in the hearts and thoracic aortae of non-exercised rats. Co-administration of melatonin and HRT to exercised OVX rats reduced inflammatory response and upregulated SIRT1 expression in the aortic and cardiac tissues. The present study suggests that melatonin treatment, either alone or in combination with exercise and/or HRT, upregulates SIRT1 expression and alleviates oxidative injury and inflammation in the hearts and aortas of OVX rats. Melatonin should be considered in alleviating cardiovascular disease risk in postmenopausal women.
... 14) However, the mechanism involved in EPinduced cardio-protection still remains controversial, such as increased heat shock protein production, increased cardiac antioxidant capacity, and improvement in ATPdependent potassium channel function. [15][16][17] In the present study, we focused on the differentially expressed miRNAs during EP-attenuating cardiac hypertrophy, and we analyzed the function annotation of their potential target genes. The result would provide valuable clues for the internal mechanism of miRNA-mediated regulation of cardiac hypertrophy. ...
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Exercise preconditioning (EP) attenuates pathological cardiac hypertrophy by increasing the functional capacity of the cardiovascular system; however, the underlying molecular mechanisms remain unclear. MicroRNAs (miRNAs) play important roles in various physiological and pathological processes by regulating the expression of the targeted gene. In this study, we aimed to screen the miRNAs involved in EP-attenuating pathological cardiac hypertrophy. The histological and echocardiographic parameters assessment showed that pathological cardiac hypertrophy induced by transverse aortic constriction (TAC) was significantly alleviated in EP treated rats. The left ventricular tissues (n = 3) from Sham, TAC and EP + TAC groups were subjected to small RNA deep sequencing. A total of 570 known mature miRNAs and 530 putative novel miRNAs were detected. DEGseq analysis showed that there were 37 and 88 differentially expressed miRNAs in the comparisons of TAC versus Sham and EP + TAC versus TAC, respectively. Among them, EP treatment could relieve the expression changes of 32 miRNAs, which were supposed to be involved in EP-attenuating pathological cardiac hypertrophy. After miRNAs target genes prediction by miRDB algorithm, pathway analysis showed that the most frequently represented pathways were involved in Calcium signaling pathway and MAPK signaling pathway. The results would provide valuable clues to finding therapeutic targets for the treatment of pathological cardiac hypertrophy.
... Moderate-intensity exercise in aged rats increase CSE and 3-MST expression in the heart, thus increasing H 2 S availability, while lowering oxidative stress and fibrosis [172]. In ovariectomized rats, which have reduced CSE expression, exercise augmented the damage induced by heart failure and restored CSE expression [173]. Although H 2 S production was not evaluated, these results suggest a role of H 2 S by altering the flux of metabolites in the reverse transsulfuration pathway. ...
Article
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Cardiovascular disease is the leading cause of death in the U.S. While various studies have shown the beneficial impact of exogenous hydrogen sulfide (H2S)-releasing drugs, few have demonstrated the influence of endogenous H2S production. Modulating the predominant enzymatic sources of H2S—cystathionine-β-synthase, cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase—is an emerging and promising research area. This review frames the discussion of harnessing endogenous H2S within the context of a non-ischemic form of cardiomyopathy, termed diabetic cardiomyopathy, and heart failure. Also, we examine the current literature around therapeutic interventions, such as intermittent fasting and exercise, that stimulate H2S production.
... [1][2][3][4][5][6][7][8] And a metaanalysis of randomized trials showed that exercise training for patients with heart failure improved exercise capacity and reduced cardiovascular events. 1,[9][10][11] However, continuous moderate-intensity aerobic training is only limited to patients with preserved exercise capacity and muscle strength. Patients with severe deconditioning or muscle weakness are intolerant to continuous moderate-intensity aerobic training. ...
Article
Aerobic training based on anaerobic threshold (AT) is well-known to improve cardiac function, exercise capacity, and long-term outcomes of patients with heart failure. Recent reports suggested that high-intensity interval training (HIIT) for patients with cardiovascular disease may improve cardiopulmonary exercise capacity. We present a 61-year-old male patient of severe left ventricular dysfunction with left ventricular assisted device (LVAD). Following HIIT for 8 weeks, exercise capacity and muscle strength have improved without worsening left ventricular function. Our case showed the possibility that HIIT was feasible and effective even in patients with LVAD.
... The recent study indicated that chronic aerobic exercise increased the H 2 S bioavailability in aged rats [143]. Also, exercise could stimulate the various enzymes that produce H 2 S including CSE (cystathionine γlyase), CBS (cystathionine β-synthase) and 3MST (3-mercaptopyruvate sulfurtransferase) [144,145], but it should be established with aging situation. Recently, H 2 S slows aging by inhibiting free radical production, activating Sirt1 through KLOTHO gene [141]. ...
Article
Oxidative stress is the core of most pathological situations, and its attribution toward disease conversion is not yet well established. The adaptive capacity of a cell can overcome ROS-induced pathology. However, when a cell fails to extend its maximum adaptive capacity against oxidative stress, it could lead a cell to misbehave or defunct from its normal functions. Any type of physical activity can increase the cells' maximum adaptive capacity, but aging can limit this. However, whether aging is the initiating point of reducing cells' adaptive capacity against oxidative stress or oxidative stress can induce the aging process is a mystery, and it could be the key to solving several uncured diseases. Paradoxically, minimum ROS is needed for cellular homeostasis. Nevertheless, finding factors that can limit or nullify the production of ROS for cellular homeostasis is a million-dollar question. Regular physical exercise is considered to be one of the factors that can limit the production of ROS and increase the ROS-induced benefits in the cells through inducing minimum oxidative stress and increasing maximum adapting capacity against oxidative stress-induced damages. The type and intensity of exercise that can produce such positive effects in the cells remain unclear. Therefore, this review discusses how physical exercise can help to produce minimal positive oxidative stress in preventing skeletal muscle aging.
... Studies have shown that exercise increases the amount of H2S contents in the cardiac and aortic endothelial cells, as well as cystathionine γ-lyase (CSE) gene expression, which itself is a key enzyme in the production of H2S in hypertensive (11) and ovariectomized rats (12). ...
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Physical exercise is shown to have protective effects on chronic kidney disease (CKD). CKD itself is associated with a reduction in renal hydrogen sulfide (H2S) concentration. This study was designed to investigate whether protective effects of exercise in 5/6 nephrectomized (5/6 NX) rats is associated with H2S levels in the kidney? Twenty four male Wistar rats weighing 250–300 g were assigned into 4 groups: 1- Sham 2- Sham exercise 3–5/6 NX 4–5/6 NX+exercise. To induce CKD, 4 days after removing upper and lower one-third parts of the left kidney, total right nephrectomy was performed. In the Sham groups, anesthesia and surgery were performed like the other groups without removal of the kidney mass. Exercise was performed by treadmill at a speed of 18 m/min for 8 weeks. At the end of the twelfth week, blood and kidney samples were collected to measure renal function (levels of plasma urea and creatinine), oxidative stress markers (renal MDA level and SOD activity), and histological indices. Eight weeks exercise significantly improved serum creatinine, BUN, renal MDA level, SOD activity, renal sympathetic nerve activity (RSNA), hypertension, and renal histology in addition to renal H2S level compared to the 5/6 NX group. The results suggest that regular exercise improves renal oxidative status and ameliorates renal damage, hypertension, and RSNA in 5/6 nephrectomized rats. These improvements by exercise might be associated with the increase in renal H2S level.
... It is suggested that estradiol is protective against oxidative damage prior to menopause [9]. Numerous in vivo studies performed in the rat model of menopause induced by bilateral ovariectomy have shown that, under estrogen deficiency, the oxidative-antioxidative balance is disturbed, which manifests in the changes in antioxidative parameters, both enzymatic and nonenzymatic, as well as in oxidative damage parameters in various organs [42,[47][48][49][50][51][52][53][54]. However, the number of reports on the measurement of those parameters in the serum of ovariectomized experimental animals is less numerous [42,[54][55][56][57][58]. ...
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Sinapic acid is a natural phenolic acid found in fruits, vegetables, and cereals, exerting numerous pharmacological effects. The aim of the study was to investigate the influence of sinapic acid on biochemical parameters related to glucose and lipid metabolism, as well as markers of antioxidant abilities and parameters of oxidative damage in the blood serum in estrogen-deficient rats. The study was performed on 3-month-old female Wistar rats, divided into 5 groups, including sham-operated control rats, ovariectomized control rats, and ovariectomized rats administered orally with estradiol (0.2 mg/kg) or sinapic acid (5 and 25 mg/kg) for 28 days. The levels of estradiol, progesterone, interleukin 18, insulin, glucose, fructosamine, lipids, and enzymatic and nonenzymatic antioxidants (superoxide dismutase, catalase, and glutathione); total antioxidant capacity; and oxidative damage parameters (thiobarbituric acid-reactive substances, protein carbonyl groups, and advanced oxidation protein products) were determined in the serum. Estradiol counteracted the carbohydrate and cholesterol metabolism disorders induced by estrogen deficiency. Sinapic acid increased the serum estradiol concentration; decreased insulin resistance and the triglyceride and total cholesterol concentrations; and favorably affected the parameters of antioxidant abilities (reduced glutathione, superoxide dismutase) and oxidative damage (advanced oxidation protein products).
... Oxidative stress may serve an important pathophysiological role during the menopause, and is considered one of the main causative factors of various cardiovascular disorders, including postmenopausal cardiovascular disorders (24,25). A number of studies have demonstrated that OVX may result in a decrease in antioxidative biomarkers and an increase in MDA content (oxidative biomarker) in the myocardium (26,27). SOD, CAT and GSH comprise the antioxidant defense system; SOD and CAT are important components of this system. ...
Article
Previous studies have demonstrated that ovariectomy may lead to a reduction in antioxidative biomarkers in the myocardium, thus suggesting that estrogens may serve a protective role in the suppression of oxidative stress. Lycium barbarum polysaccharides (LBP) are a well-known antioxidant Chinese traditional medicine, which appear to have a similar function to estrogens with regards to the regulation of cardiac function. In the present study, 30 Sprague-Dawley rats were randomly divided into the following groups: Sham operation group, ovariectomized (OVX) group, estradiol valerate group, high-dose LBP (LBP-H) group and low-dose LBP (LBP-L) group. All of the rats were provided tap water, estradiol valerate or LBP for 12 weeks. In addition, all rats were ovariectomized, with the exception of rats in the sham operation group, which underwent fat removal only. Reactive oxygen species (ROS), malondialdehyde (MDA), glutathione peroxidase (GSH-px), catalase (CAT) and superoxide dismutase activities were subsequently examined. The protein expression levels of cleaved caspase-9, cleaved caspase-3 and phosphorylated-protein kinase B (p-Akt) were also assessed. The results demonstrated that high-dose LBP decreased the enhanced levels of ROS and MDA in OVX rats, whereas GSH-px and CAT activities were increased in the LBP-H group compared with in OVX rats. Furthermore, the expression levels of cleaved caspase-9 and cleaved caspase-3 were significantly upregulated in the OVX group, whereas high-dose LBP exerted protective effects on OVX rats by decreasing the expression of apoptotic proteins. Conversely, p-Akt expression was decreased in the OVX group and was increased in the LBP-H group. These results indicated that LBP is essentially involved in cardiac protection by inhibiting apoptosis in response to oxidative stress. In addition, improvement of antioxidant status by LBP is associated with the Akt signaling pathway in the myocardium of OVX rats.
... The ovariectomized (OVX) rat is a suitable animal model to mimic the estrogen withdrawal of postmenopausal women [15,16]. Some studies had shown OVX rat could undergo myocardial injury induced by ovariectomy [17][18][19], and estrogen had a protective effect against this myocardial injury [20,21]. Er-Xian Decoction (EXD), a Chinese herbal formula, has been proven to reduce the severity and frequency of hot flushes and ameliorate menopausal symptoms in perimenopausal women without serious adverse events [22]. ...
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Background: Er-Xian decoction (EXD), a formula of Chinese medicine, is often used to treat menopausal syndrome in China. The aim of the present study was to explore the potential cardioprotective mechanism of EXD against myocardial injury in an ovariectomy-induced menopausal rat model. Methods: We divided the female Wistar rats into ovariectomy group and sham operation group (SHAM group). The ovariectomized (OVX) rats received treatment of vehicle (OVX group), EXD (EXD group) or 17β-estradiol (E2 group). After 12-week of treatment, the level of estradiol in serum was detected using an electrochemiluminescence immunoassay, and electrophysiologic changes in myocardial action potentials (AP) were evaluated using intracellular microelectrode technique. Changes in the histopathology of the left ventricle and the ultrastructure of the cardiomyocytes were observed by hematoxylin and eosin (HE) staining and transmission electronmicroscopy to assess myocardial injury. Microarrays were applied for the evaluation of gene expression profiles in ventricular muscle of the OVX and EXD rats. Further pathway analyses of the differential expression genes were carried out using the Kyoto Encyclopedia of Genes and Genomes (KEGG). And real-time quantitative RT-PCR (qRT-PCR) was used for verification of the key findings. Results: The results from electrophysiological and histomorphological observations demonstrated that EXD had a substantial myocardial protective effect. The EXD-treated rats, in comparison with the OVX rats, demonstrated up-regulated expression of 28 genes yet down-regulated expression of 157 genes in the ventricular muscle. The qRT-PCR assay validated all selected differential expression genes. The KEGG pathway analysis showed that the down-regulated genes were relevant to cardiomyopathy and myocardial contractility. EXD could decrease the mRNA expressions of cardiac myosin (Myh7, Myl2) and integrin (Itgb5) in the ventricular myocardium. Conclusion: EXD had a protective effect against myocardial injury in OVX rats, and this cardioprotective effect may be associated with modulation of the expression of cardiac myosin or integrin at the mRNA level.
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Over the last decade, hydrogen sulfide (H2S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide,H2S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H2S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H2S, either based on H2S donation or inhibition ofH2S biosynthesis.H2S donation can be achieved through the inhalation of H2S gas and/or the parenteral or enteral administration of so-called fast-releasing H2S donors (salts of H2S such as NaHS and Na2S) or slow-releasingH2S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H2S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H2S-donating groups (the most advanced compound in clinical trials is ATB-346, anH2S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition ofH2S synthesis, there are now several small molecule compounds targeting each of the three H2S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), thesemolecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H2S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H2S donors and H2S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility. © 2017 by The American Society for Pharmacology and Experimental Therapeutics.
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Background In general, postmenopausal women present higher mortality, and worse prognosis after myocardial infarction compared to men, due to estrogen deficiency. After MI, cardiovascular alterations occur, such as the autonomic imbalance and the pro-inflammatory cytokines increase. In this sense, therapies that aim to minimize deleterious effects caused by ischemia are important. Aerobic training has been proposed as a promising intervention in the prevention of cardiovascular diseases. On the other hand, some studies have attempted to identify potential biomarkers for cardiovascular deseases or specifically for myocardial infarction. For this purpose, metabolomics has been used as a tool in the discovery of cardiovascular biomarkers. Objective Therefore, the objective of this work is to discuss the changes involved in ovariectomy, myocardial infarction, and aerobic training, with emphasis on inflammation and metabolism.
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Aims Clinical trials have shown the beneficial effects of exercise training against pulmonary fibrosis. This study aimed to investigate whether prophylactic intervention with exercise training attenuates lung fibrosis via modulating endogenous hydrogen sulfide (H2S) generation. Methods Firstly, ICR mice were allocated to Control, Bleomycin, Exercise, and Bleomycin+Exercise groups. Treadmill exercise began on day 1 and continued for 4 weeks. A single intratracheal dose of bleomycin (3 mg/kg) was administered on day 15. Secondly, ICR mice were allocated to Control, Bleomycin, H2S, and Bleomycin+H2S groups. H2S donor NaHS (28 umol/kg) was intraperitoneally injected once daily for two weeks. Results Bleomycin‐treated mice exhibited increased levels of collagen deposition, hydroxyproline, collagen I, transforming growth factor (TGF)‐β1, Smad2/Smad3/low‐density lipoprotein receptor‐related proteins (LRP‐6)/glycogen synthase kinase‐3β (GSK‐3β) phosphorylation, and Smad4/β‐catenin expression in lung tissues (p<0.01), which was alleviated by exercise training (p<0.01 except for Smad4 and phosphorylated GSK‐3β: p<0.05). Bleomycin‐induced lung fibrosis was associated with increased α smooth muscle actin (α‐SMA) and decreased E‐cadherin expression (p<0.01). Double immunofluorescence staining showed the co‐localization of E‐cadherin/α‐SMA, indicating epithelial‐mesenchymal transition (EMT) formation, which was ameliorated by exercise training. Moreover, exercise training restored bleomycin‐induced downregulation of cystathionine‐β‐synthase (CBS) and cystathionine‐γ‐lyase (CSE) expression, as well as H2S generation in lung tissue (p<0.01). NaHS treatment attenuated bleomycin‐induced TGF‐β1 production, activation of LRP‐6/β‐catenin signaling, EMT and lung fibrosis (p<0.01 except for β‐catenin: p<0.05). Conclusion Exercise training restores bleomycin‐induced downregulation of pulmonary CBS/CSE expression, thus contributing to the increased H2S generation and suppression of TGF‐β1/Smad and LRP‐6/β‐catenin signaling pathways, EMT and lung fibrosis. This article is protected by copyright. All rights reserved.
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Hydrogen sulfide (H2S) has been known for its toxicity. However, recent studies have focused on the mechanisms involved in endogenous production and function. To date, the H2S role in insulin signaling and glucose homeostasis is unclear. This uncertainty is even more evident in skeletal muscle, a physiological niche highly relevant for regulating glycemia in response to insulin. This study aimed to investigate the role of H2S on insulin signaling and glucose uptake in the L6 skeletal muscle cell line. We evaluated the endogenous synthesis with the fluorescent dye, 7-azido-4-methyl coumarin (7-AzMC). Glucose restriction-induced an increase in the endogenous levels of H2S, likely through stimulation of cystathionine γ-lyase activity, as its specific inhibitor, PAG (5 mM) prevented this increase, and mRNA levels of CSE decreased with glucose and amino acid restriction. Exogenous H2S reduced insulin-induced glucose uptake at 0.5 up to 24 h, an effect dissociated from the level of Akt phosphorylation. Our results show that glucose restriction induces endogenous production of H2S via CSE. In addition, H2S disrupts insulin-induced glucose uptake independent of the Akt pathway. These results suggest that H2S antagonism over insulin-induced glucose uptake could help maintain the plasmatic glucose levels in conditions that provoke hypoglycemia, which could serve as an H2S-regulated mechanism for maintaining glucose plasmatic levels through the inhibition of the skeletal muscle insulin-depended glucose uptake.
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The aim of this study was to evaluate the effects of swimming training (SW) and oestrogen replacement therapy (ERT) on coronary vascular reactivity and the expression of antioxidant enzymes in ovariectomized rats. Animals were randomly assigned to one of five groups: sham (SH), ovariectomized (OVX), ovariectomized with E2 (OE2), ovariectomized with exercise (OSW), and ovariectomized with E2 plus exercise (OE2+SW). The SW protocol (5×/week, 60 min/day) and/or ERT were conducted for 8 weeks; the vasodilator response to bradykinin was analysed (Langendorff Method), and the expression of antioxidant enzymes (SOD-1 and 2, catalase) and eNOS and iNOS were evaluated by Western blotting. SW and ERT improved the vasodilator response to the highest dose of bradykinin (1000 ng). However, in the OSW group, this response was improved at 100, 300 and 1000 ng when compared to OVX (p<0,05). The SOD-1 expression was increased in all treated/trained groups compared to the OVX group (p<0,05), and catalase expression increased in the OSW group only. In the trained group, eNOS increased vs. OE2, and iNOS decreased vs. SHAM (p<0,05). SW may represent an alternative to ERT by improving coronary vasodilation, most likely by increasing antioxidant enzyme and eNOS expression and augmenting NO bioavailability.
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The aim of this study was to evaluate the potential influence of endogenous ovarian hormones on cardiac oxidative stress in renovascular hypertension. Female Wistar rats (N = 10 per group) were divided among 4 groups: (i) normotensive control; (ii) hypertensive control; (iii) normotensive ovariectomized; and (iv) hypertensive ovariectomized rats. To induce hypertension, 2-kidney 1-clip (2K1C) Goldblatt's method was followed. Blood pressure (BP) was enhanced (25%) in 2K1C and it was not further altered in hypertensive ovariectomized animals. Lipid peroxidation (measured by thiobarbituric acid reactive substances; TBARS) increased in heart homogenates after ovariectomy (253%) and was additionally augmented when associated with hypertension (by 28%). Superoxide dismutase and catalase activities were similar in both hypertensive groups. Hypertension enhanced glutathione peroxidase activity (75%), but the association with ovariectomy prevented this change. Total radical trapping antioxidant potential (TRAP) decreased in hypertensive rats (34%) and was recovered when associated with ovariectomy. However, this adaptation seems not to be sufficient to avoid the increased oxidative damage in ovariectomized hypertensive animals. These results suggest a protective role for physiological ovarian hormones in the cardiac oxidative stress induced by 2K1C hypertension.
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Nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) are lipid-soluble, endogenously produced gaseous messenger molecules collectively known as gasotransmitters. Over the last several decades, gasotransmitters have emerged as potent cytoprotective mediators in various models of tissue and cellular injury. Specifically, when used at physiological levels, the exogenous and endogenous manipulation of these three gases has been shown to modulate ischemia/reperfusion injury by inducing a number of cytoprotective mechanisms including: induction of vasodilatation, inhibition of apoptosis, modulation of mitochondrial respiration, induction of antioxidants, and inhibition of inflammation. However, while the actions are similar, there are some differences in the mechanisms by which these gasotransmitters induce these effects and the regulatory actions of the enzyme systems can vary depending upon the gas being investigated. Furthermore, there does appear to be some crosstalk between the gases, which can provide synergistic effects and additional regulatory effects. This review article will discuss several models and mechanisms of gas-mediated cytoprotection, as well as provide a brief discussion on the complex interactions between the gasotransmitter systems.
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From human and animal studies, estrogen is known to protect the myocardium from an ischemic insult. However, there is limited knowledge regarding mechanisms by which estrogen directly protects cardiomyocytes. In this report, we employed an in vitro model, in which cultured rat cardiomyocytes underwent prolonged hypoxia followed by reoxygenation (H/R), to study the cardioprotective mechanism of estrogen. 17-β-estradiol (E2) acting via estrogen receptors inhibited H/R-induced apoptosis of cardiomyocytes. Mitochondrial reactive oxygen species (ROS) generated from H/R activated p38α MAPK, and inhibition of p38α with SB203580 significantly prevented H/R-induced cell death. E2 suppressed ROS formation and p38α activation by H/R and concomitantly augmented the activity of p38β. Unlike p38α, p38β was little affected by H/R. Dominant negative p38β protein expression decreased E2-mediated cardiomyocyte survival and ROS suppression during H/R stress. The prosurvival signaling molecule, phosphoinositol-3 kinase (PI3K), has previously been linked to cell survival following ischemia-reperfusion injury. Here, E2-activated PI3K was found to inhibit ROS generated from H/R injury, leading to inhibition of downstream p38α. We further linked these signaling pathways in that p38β was activated by E2 stimulation of PI3K. Thus, E2 differentially modulated two major isoforms of p38, leading to cardiomyocyte survival. This was achieved by signaling through PI3K, integrating cell survival mediators.
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In Reply. —Dr Sullivan chastises us for an overemphasis on the role of lipids in mediating the protective effect of estrogen. We plead not guilty as charged; in our review we wrote: "These two reports suggest that between 25% and 50% of the beneficial effect of estrogen on CHD [coronary heart disease] risk is through changes in HDL [high-density lipoprotein] and LDL [low-density lipoprotein] cholesterol. However, this further implies that 50% to 75% of the beneficial effect of estrogen is through other, nonlipid mechanisms." We listed about 10 other possible mechanisms, but made no attempt to list all possible ways in which estrogen could reduce the risk of heart disease. Sullivan suggests lower levels of iron, caused by menstrual blood loss, as a possible explanation for the sex differences in heart disease, an interesting but as yet untested hypothesis.Sullivan notes that women with hypercholesterolemia have a lower risk of
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We review herein the evidence that estrogen is protective against the development of cardiovascular disease in women. To our knowledge, no studies in women have looked at endogenous estrogen levels as predictors of cardiovascular disease. Studies of surrogate measures of endogenous estrogen such as parity, age at menarche, and age at menopause have provided inconsistent results. Current use of oral contraceptives increases risk in older women who smoke cigarettes, but most studies of past use show no increased risk. Most, but not all, studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen. These important observations need to be confirmed in a double-blind, randomized clinical trial, since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded. (JAMA. 1991;265:1861-1867)
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Estrogens have been suggested to exert cardioprotection through maintaining endogenous cardioprotective mechanisms. In present study, we investigated whether estrogens protect cardiomyocytes against hypoxia/reoxygenation (H/R) via modulating urocortins (UCNs) and their receptor corticotrophin-releasing hormone receptor type 2 (CRHR2). We found that 17β-estradiol (E2) enhanced UCN cardioprotection against H/R and increased CRHR2 expression in neonatal rat cardiomyocytes. E2 protected cardiomyocytes against H/R, which was impaired by CRHR2 antagonist or knockdown of CRHR2. Estrogen receptor α (ERα) antagonist treatment or ERα knockdown could abolish E2-induced CRHR2 up-regulation. Moreover, knockdown of Sp1 also attenuated E2-indueced CRHR2 up-regulation. Ovariectomy resulted in down-regulation of CRHR2 and Sp-1 in myocardium of mice, which was restored by E2 or ERα agonist treatment. These results suggest that estrogens act on ERα to up-regulate CRHR2 expression in cardiomyocytes, thereby enhancing cardioprotection of UCNs against H/R.
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Objective: Hydrogen sulfide (H2S), generated in the myocardium predominantly via cystathionine-γ-lyase (CSE), is cardioprotective. The objectives of the present study were to investigate the effects of estrogens on CSE expression and H2S generation in the myocardium and to examine whether serum 17β-estradiol (E2) level is associated with CSE activity and H2S generation and whether H2S or E2 level is associated with proinflammatory cytokines and oxidative stress status. Methods: Ovariectomized Sprague-Dawley rats received subcutaneous E2 (30 μg/kg/d) or vehicle for 12 weeks. At the end of the 12-week treatment, CSE expression, H2S generation, reduced glutathione/oxidized glutathione (GSH/GSSG) ratio, total antioxidant capacity (T-AOC), superoxide dismutase (SOD) activity, catalase (CAT) activity, interleukin (IL)-6 concentration, and tumor necrosis factor-α (TNF-α) concentration in the left ventricle were determined. Results: E2 increased CSE expression and H2S generation in the myocardium of ovariectomized rats. H2S production rate and serum E2 were positively correlated. E2 increased GSH/GSSG ratio, T-AOC, CAT, and SOD activity but decreased IL-6 and TNF-α levels. Serum E2 level was positively correlated with GSH/GSSG ratio, T-AOC, CAT, and SOD activity, and inversely correlated with IL-6 and TNF-α levels. H2S generation rate was positively correlated with T-AOC and GSH/GSSG ratio, and inversely correlated with IL-6 and TNF-α levels. Conclusions: E2 increases CSE expression and endogenous H2S generation in the myocardium. The effects of E2 are associated with decreased oxidative stress and inflammatory status. Our data suggest that estrogens might exert cardioprotective effects through up-regulation of CSE expression and H2S generation.
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Recent research has shown that the endogenous gas hydrogen sulphide (H2S) is a signalling molecule of considerable biological potential and has been suggested to be involved in a vast number of physiological processes. In the vascular system, H2S is synthesized from cysteine by cystathionine-γ-lyase (CSE) in smooth muscle cells (SMC) and 3- mercaptopyruvate sulfuresterase (3MST) and CSE in the endothelial cells. In pulmonary and systemic arteries, H2S induces relaxation and/or contraction dependent on the concentration of H2S, type of vessel and species. H2S relaxes SMC through a direct effect on KATP-channels or Kv-channels causing hyperpolarization and closure of voltage-dependent Ca2+-channels followed by a reduction in intracellular calcium. H2S also relaxes SMC through the release of endothelium- derived hyperpolarizing factor (EDHF) and nitric oxide (NO) from the endothelium. H2S contracts SMC through a reduction in nitric oxide (NO) availability by reacting with NO forming a nitrosothiol compound and through an inhibitory effect on endothelial nitric oxide synthase (eNOS) as well as a reduction in SMC cyclic AMP concentration. Evidence supports a role for H2S in oxygen sensing. Furthermore, reduced endogenous H2S production may also play a role in ischemic heart diseases and hypertension, and treatment with H2S donors and cysteine analogues may be beneficial in treatment of cardiovascular disease.
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Estrogen has pleiotropic effects on the cardiovascular system. The mechanisms by which estrogen confers these pleiotropic effects are undergoing active investigation. Until a decade ago, all estrogen signaling was thought to occur by estrogen binding to nuclear estrogen receptors (estrogen receptor-α and estrogen receptor-β), which bind to DNA and function as ligand-activated transcription factors. Estrogen binding to the receptor alters gene expression, thereby altering cell function. Estrogen also binds to nuclear estrogen receptors that are tethered to the plasma membrane, resulting in acute activation of signaling kinases such as PI3K. An orphan G-protein-coupled receptor, G-protein-coupled receptor 30, can also bind estrogen and activate acute signaling pathways. Thus, estrogen can alter cell function by binding to different estrogen receptors. This article reviews the different estrogen receptors and their signaling mechanisms, discusses mechanisms that regulate estrogen receptor levels and locations, and considers the cardiovascular effects of estrogen signaling.
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To explore the mechanism(s) of exercise training on ovariectomized (OVX)-induced liver lipid disorder, we observed effects of treadmill training on liver fat accumulation and ER alpha expression in intact and ovariectomized rats. Sixty female rats were randomly assigned to six groups: Sham sedentary (S-S), Sham exercised (S-EX), ovariectomized sedentary (O-S), ovariectomized exercised (O-EX), ovariectomized injected subcutaneously with 17beta-estradiol (E(2)) (O-E(2)), and ovariectomized treated with E(2) and exercise (O-E(2)-EX). Twelve weeks after intervention, OVX resulted in significantly higher body weight gain, intra-abdominal fat mass, serum levels of total cholesterol (TC), and liver triacylglycerol (TAG) concentrations and ER alpha expression than S-S group, while the relative uterus and liver mass, serum levels of E(2), TAG, and the ratio of high density lipoprotein (HDL) to TC were markedly lower in O-S group. All of these changes were decreased in O-S rats after treatment with E(2) alone with the exception of serum TC and HDL-C levels and liver ER alpha expression. Exercise alone significantly reversed the effect of OVX on serum E(2), the ratio of HDL-C to TC and the liver and intra-abdominal fat accumulation in OVX rats. The addition of E(2) to exercise induced the same uterus and lipid profile as E(2) alone. Moreover, an additive effect of exercise and E(2) was observed on liver ER alpha expression in Sham or OVX rats. In conclusion, treadmill training alone could prevent liver fat accumulation in OVX rats and the regulation of exercise on liver ER alpha expression in both OVX and Sham rats needs the presence of physical estrogen levels.
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Reactive oxygen and nitrogen species (ROS and RNS, respectively) generate nitrotyrosine and activate latent resident myocardial matrix metalloproteinases (MMPs). Although in chronic heart failure (CHF) there is robust increase in ROS, RNS, and MMP activation, recent data suggest that hydrogen sulfide (H(2)S, a strong antioxidant gas) is cardioprotective. However, the role of H(2)S in mitigating oxidative and proteolytic stresses in cardiac remodeling/apoptosis in CHF was unclear. To test the hypothesis that H(2)S ameliorated cardiac apoptosis and fibrosis by decreasing oxidative and proteolytic stresses, arteriovenous fistula (AVF) was created in wild-type (C57BL/6J) mice. The hearts were analyzed at 0, 2, and 6 wk after AVF. To reverse the remodeling, AVF mice were treated with NaHS (an H(2)S donor, 30 micromol/l in drinking water) at 8 and 10 wk. The levels of MMPs were measured by gelatin-gel zymography. The levels of nitrotyrosine, tissue inhibitors of metalloproteinase (TIMPs), beta(1)-integrin, and a disintegrin and metalloproteinase-12 (ADAM-12) were analyzed by Western blots. The levels of pericapillary and interstitial fibrosis were identified by Masson trichrome stains. The levels of apoptosis were measured by identifying the TdT-mediated dUTP nick end labeling (TUNEL)-positive cells and caspase-3 levels. The results suggested robust nitrotyrosine and MMP activation at 2 and 6 wk of AVF. The treatment with H(2)S donor mitigated nitrotyrosine generation and MMP activation (i.e., oxidative and proteolytic stresses). The levels of TIMP-1 and TIMP-3 were increased and TIMP-4 decreased in AVF hearts. The treatment with H(2)S donor reversed this change in TIMPs levels. The levels of ADAM-12, apoptosis, and fibrosis were robust and integrin were decreased in AVF hearts. The treatment with H(2)S donor attenuated the fibrosis, apoptosis, and decrease in integrin.
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Three hundred years have passed since the first description of the toxicity of hydrogen sulfide (H(2)S). Three papers in 1989 and 1990 described relatively high concentrations of sulfide in the brain. In 1996 we demonstrated that cystathionine beta-synthase (CBS) is a H(2)S producing enzyme in the brain and that H(2)S enhances the activity of NMDA receptors and facilitates the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory. In the following year, we demonstrated that another H(2)S producing enzyme, cystathionine gamma-lyase is in the thoracic aorta, portal vein, and the ileum, and that H(2)S relaxes these tissues. Based on these observations we proposed H(2)S as a neuromodulator as well as a smooth muscle relaxant. We recently demonstrated that the third H(2)S-producing enzyme, 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase (CAT) produces H(2)S in the brain as well as in vascular endothelium. Various functions in many tissues have been proposed. H(2)S protects neurons and cardiac muscle from oxidative stress. H(2)S has pro- and anti-inflammatory effects, nociceptive effects, the regulatory function of insulin release, and is even involved in longevity. Recent progress in the studies of physiological functions of H(2)S in neurons and smooth muscle was described.
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We review herein the evidence that estrogen is protective against the development of cardiovascular disease in women. To our knowledge, no studies in women have looked at endogenous estrogen levels as predictors of cardiovascular disease. Studies of surrogate measures of endogenous estrogen such as parity, age at menarche, and age at menopause have provided inconsistent results. Current use of oral contraceptives increases risk in older women who smoke cigarettes, but most studies of past use show no increased risk. Most, but not all, studies of hormone replacement therapy in postmenopausal women show around a 50% reduction in risk of a coronary event in women using unopposed oral estrogen. These important observations need to be confirmed in a double-blind, randomized clinical trial, since the protection is biologically plausible and the magnitude of the benefit would be quite large if selection factors can be excluded.
Article
Effects of an antioxidant, vitamin E, and a membrane stabilizing agent, zinc, were examined on the isoproterenol-induced changes in the rat myocardium. Isoproterenol treatment (80 mg/kg given over 2 days in two equal doses) caused arrhythmias and 25% mortality within 24 h of the last injection. The ultrastructural changes in the subendocardium and in focal areas of the subepicardium included swelling of mitochondria, loss of myofibrils, cell necrosis, fibrosis, and infiltration of the affected areas by polymorphonucleocytes. Both creatine phosphate and adenosine triphosphate levels were markedly decreased in hearts from isoproterenol-treated animals. Pretreatment of the animals with vitamin E (10 mg X kg-1 X day -1 for 2 weeks) or zinc (10 mg/kg ZnSO4, twice a day for 7 days) prevented these deleterious effects of isoproterenol. Animals maintained on vitamin E deficient diet for 8 weeks were found to be more sensitive to isoproterenol-induced changes and this increased sensitivity was reversed by a 2-week feeding of the animals on the normal diet coupled with vitamin E treatment. Based on the data obtained in this study it is proposed that catecholamine-induced changes may involve free radicals, which by promoting lipid peroxidation may increase membrane permeability and lead to the development of cardiomyopathy.
Article
Menopause is a normal aging phenomenon in women and consists of the gradual transition from the reproductive to the non-reproductive phase of life. The median age at the menopause is currently around 50 years. As a result of the increasing life expectancy in the first and second worlds, many women will be postmenopausal for over one-third of their lives. The influence of menopause per se on blood pressure remains uncertain. Recent experimental and epidemiological evidence supports the hypothesis that oestrogen deficiency may induce endothelial and vascular dysfunction and potentiate the age-related increase in systolic pressure, possibly as a consequence of a reduced compliance of the large arteries. However, the latter hypothesis requires further investigation.
Article
Lifestyle modifications, such as physical activity, are recommended as first-line or adjunctive therapy for hypertension. However, controversy exists regarding the type, amount, and intensity of physical activity for optimal blood pressure lowering. This study evaluated the blood pressure changes in 18 post-menopausal, sedentary, untreated hypertensive women randomized to an individualized 8-week programme of intermittent moderate-intensity physical activity versus no change in physical activity. The physical activity group was asked to select activities (such as walking) to engage in physical activity for 10 min, three times a day, 5 days per week at an intensity of 50-60% heart rate reserve. Independent T-tests were used to compare the difference in resting blood pressure between groups. After 8 weeks, resting blood pressure was 8/5 mmHg lower in the physical activity group (systolic blood pressure, P= 0.006 and diastolic blood pressure, P = 0.059). The between group differences remained significant after adjustment for age, baseline blood pressure and previous use of antihypertensive drug therapy. These data show that hypertensive, post-menopausal women who engage in intermittent, moderate-intensity physical activity experience a reduction in blood pressure.
Article
The Heart and Estrogen/progestin Replacement Study (HERS) found no overall reduction in risk of coronary heart disease (CHD) events among postmenopausal women with CHD. However, in the hormone group, findings did suggest a higher risk of CHD events during the first year, and a decreased risk during years 3 to 5. To determine if the risk reduction observed in the later years of HERS persisted and resulted in an overall reduced risk of CHD events with additional years of follow-up. Randomized, blinded, placebo-controlled trial of 4.1 years' duration (HERS) and subsequent unblinded follow-up for 2.7 years (HERS II) conducted at outpatient and community settings at 20 US clinical centers. A total of 2763 postmenopausal women with CHD and average age of 67 years at enrollment in HERS; 2321 women (93% of those surviving) consented to follow-up in HERS II. Participants were randomly assigned to receive 0.625 mg/d of conjugated estrogens and 2.5 mg of medroxyprogesterone acetate (n = 1380), or placebo (n = 1383) during HERS; open-label hormone therapy was prescribed at personal physicians' discretion during HERS II. The proportions with at least 80% adherence to hormones declined from 81% (year 1) to 45% (year 6) in the hormone group, and increased from 0% (year 1) to 8% (year 6) in the placebo group. The primary outcome was nonfatal myocardial infarction and CHD death. Secondary cardiovascular events were coronary revascularization, hospitalization for unstable angina or congestive heart failure, nonfatal ventricular arrhythmia, sudden death, stroke or transient ischemic attack, and peripheral arterial disease. There were no significant decreases in rates of primary CHD events or secondary cardiovascular events among women assigned to the hormone group compared with the placebo group in HERS, HERS II, or overall. The unadjusted relative hazard (RH) for CHD events in HERS was 0.99 (95% confidence interval [CI], 0.81-1.22); HERS II, 1.00 (95% CI, 0.77-1.29); and overall, 0.99 (0.84-1.17). The overall RHs were similar after adjustment for potential confounders and differential use of statins between treatment groups (RH, 0.97; 95% CI, 0.82-1.14), and in analyses restricted to women who were adherent to randomized treatment assignment (RH, 0.96; 95% CI, 0.77-1.19). Lower rates of CHD events among women in the hormone group in the final years of HERS did not persist during additional years of follow-up. After 6.8 years, hormone therapy did not reduce risk of cardiovascular events in women with CHD. Postmenopausal hormone therapy should not be used to reduce risk for CHD events in women with CHD.
Article
Over the past few decades hormone replacement therapy (HRT) has been used increasingly by post-menopausal women in western countries. The need for objective data on long-term effects prompted the setting up of randomised trials to compare cancer and cardiovascular disease endpoints in HRT users and non-users. With the early termination of part of the Women's Health Initiative trial (JAMA 2002; 288: 321-33), it is timely to review the evidence from such studies. Four randomised trials including over 20000 women followed up for 4.9 years, on average, have now reported on the effect of HRT for major, potentially fatal, conditions. Overall, HRT users had a significantly increased incidence of breast cancer, stroke, and pulmonary embolism; a significantly reduced incidence of colorectal cancer and fractured neck of femur; but no significant change in endometrial cancer or coronary heart disease.There was no significant variation across the trials in the results for any condition. Three trials had recruited women with previous cardiovascular disease and the fourth, the Women's Health Initiative, had recruited healthy women. Combined oestrogen/progestagen HRT was used in three trials and oestrogen alone in one. Use of HRT over a 5-year period by healthy postmenopausal women in western countries is estimated to cause an extra breast cancer,stroke, or pulmonary embolus in about 6 per 1000 users aged 50-59 and 12 per 1000 aged 60-69. Over the same period, the estimated reduction in incidence of colorectal cancer or fractured neck of femur is 1.7 per 1000 users aged 50-59 and 5.5 per 1000 aged 60-69. The increased incidence of any one of these conditions is greater than any reduction, the estimated net excess over 5 years being 1 per 230 users aged 50-59, and 1 per 150 aged 60-69. Substantial new data should soon be available from randomised trials of oestrogen-alone HRT versus placebo, whereas few additional trial data on combined HRT are expected for about a decade. Existing randomised trials are too small to describe reliably the effect of HRT on important but rarer conditions, such as ovarian cancer, or on cause-specific mortality. Nor will they provide information about other types of oestrogen or progestagen. Answers to such questions will require judicious analysis and interpretation of data from observational studies.
Article
Hydrogen sulfide (H2S) is a well-known cytotoxic gas. Recently it has been shown to stimulate N-methyl-D-aspartate (NMDA) receptors to enhance long-term potentiation suggesting a novel neuromodulatory role in vivo. Endogenous levels of H2S in the brain are reported to range between 10 and 160 microm. Considerably lower H2S levels are reported in the brains of Alzheimer's disease (AD) patients, where levels of brain protein nitration (probably mediated by peroxynitrite) are markedly increased. Activation of NMDA receptors leads to intracellular tyrosine nitration by peroxynitrite. Because H2S and peroxynitrite are important mediators in brain function and disease, we investigated the effects of the H2S 'donor', sodium hydrogen sulfide (NaSH) on peroxynitrite-mediated damage to biomolecules and to cultured human SH-SY5Y cells. H2S significantly inhibited peroxynitrite-mediated tyrosine nitration and inactivation of alpha1-antiproteinase to a similar extent to reduced glutathione at each concentration tested (30-250 microm). H2S also inhibited peroxynitrite-induced cytotoxicity, intracellular protein nitration and protein oxidation in human neuroblastoma SH-SY5Y cells. These data suggest that H2S has the potential to act as an inhibitor of peroxynitrite-mediated processes in vivo and that the potential antioxidant action of H2S deserves further study, given that extracellular GSH levels in the brain are very low.
Article
To study the combined effects of ovariectomy and regular exercise training on hypertension and on cardiac and aortic remodeling in spontaneously hypertensive rats (SHR). Three-month-old female spontaneously hypertensive rats (SHR) were ovariectomized (ovx) or were left intact (int) and divided in four groups (n = 7): sedentary (sed-ovx), exercise-trained (ex-ovx), sedentary intact (sed-int), and exercise-trained intact (ex-int). The exercise protocol was performed on a motor treadmill for 13 weeks. Blood pressure (BP), left ventricular myocardium and aortic wall were studied by light microscopy and stereology. Exercise-trained SHR showed a BP reduction of more than 15% compared with the matched sedentary SHR (sed-int: 210 +/- 5 mm Hg, sed-ovx: 225 +/- 4 mm Hg, ex-int: 178 +/- 2 mm Hg, ex-ovx: 180 +/- 3 mm Hg, P < 0.001). Ovariectomy caused adverse cardiac and aortic wall remodeling, including cardiomyocyte hypertrophy, myocardial interstitial reparative fibrosis and vascularization impairment with loss of cardiomyocytes, and aortic tunica media hypertrophy. Exercise training showed beneficial effects, mainly reduced BP, decreased cardiac hypertrophy due to hypertension, and increased myocardial vascularization. Ovariectomy accelerated cardiomyocyte loss in SHR while exercise training offset this process. Exercise training was the main factor influencing the improvement of intramyocardial arteries length density and significantly reduced the aortic wall thickness and increased the density of smooth muscle cell nuclei per tunica media unit area. In ovariectomized SHR, exercise training exerts beneficial effects diminishing adverse cardiac and aortic wall remodeling, mainly by reducing interstitial myocardial fibrosis, improving myocardial vascularization, and sustaining the number of cardiomyocytes.
Article
Hyperhomocysteinemia (HHcy) is a critical independent risk factor for cardiovascular diseases. However, to date, no satisfactory strategies to prevent HHcy exist. Since homocysteine (Hcy) and endogenous H2S are both metabolites of sulfur-containing amino acids, we aimed to investigate whether a metabolic product of Hcy and H2S, may antagonize in part the cardiovascular effects of Hcy. In the HHcy rat model injected subcutaneously with Hcy for 3 weeks, H2S levels and the H2S-generating enzyme cystathionine gamma lyase (CSE) activity in the myocardium were decreased. The intraperitoneal injection of H2S gas saturation solution significantly reduced plasma total Hcy (tHcy) concentration and decreased lipid peroxidation formation (i.e., lowered manodialdehyde and conjugated diene levels in myocardia and plasma). The activities of myocardial mitochondrial respiratory enzymes succinate dehydrogenase, cytochrome oxidase, and manganese superoxide dismutase, related to reactive oxygen species metabolism, were significantly dysfunctional in HHcy rats. The H2S administration restored the level of enzyme activities and accelerated the scavenging of H2O2 and superoxide anion generated by Hcy in isolated mitochondria. The H2S treatment also inhibited the expression of glucose-regulated protein 78, a marker of endoplasmic reticulum (ER) stress, induced by Hcy in vivo and in vitro. Thus, HHcy impaired the myocardial CSE/H2S pathway, and the administration of H2S protected the myocardium from oxidative and ER stress induced by HHcy, which suggests that an endogenous metabolic balance of sulfur-containing amino acids may be a novel strategy for treatment of HHcy.
Article
Inflammation and the recruitment of monocytes into the artery wall are thought to be important aspects in the initiation and progression of atherosclerosis. The present study was designed to examine the effects of a rigorous diet and exercise intervention on plasma lipids and inflammatory and circulating adhesion molecules. Twenty postmenopausal women at risk for coronary artery disease (CAD) were placed on a high-fiber, low-fat diet, where food was provided ad libitum and daily aerobic exercise, primarily walking, was performed. In each subject, pre- and post-intervention fasting blood was drawn for serum lipid, insulin, glucose, C-reactive protein (CRP), serum amyloid A (SAA), interleukin-6 (IL-6) and both soluble (s) intracellular and vascular adhesion molecule (sICAM-1 and sVCAM-1) were measured. After 2 weeks, significant reductions in body mass index (BMI) (P <.001), glucose (P <.05), insulin (P <.01), all serum lipids, and total cholesterol (total-C):high-density lipoprotein-cholesterol (HDL-C) (P <.01). Reductions in homeostasis model assessment for insulin resistance (HOMA-IR) (P <.01), CRP (P <.01), SAA (P <.01) and sICAM-1 (P <.05) were noted, as well as an increase in the quantitative insulin sensitivity check index (P <.05). Reductions were also noted in 5 women not using hormone replacement therapy (HRT). No significant reductions were found in IL-6 or sVCAM-1 in response to the intervention. Overall, this intervention resulted in improved metabolic and lipid profiles, reduced inflammatory, and cell adhesion molecules in postmenopausal women in the absence of caloric restriction. The rapid improvements may reduce the risk of acute myocardial infarction (MI), and if sustained, these changes may mitigate the risk for atherosclerosis progression and its clinical consequences.