Fig 3 - uploaded by Zhengyuan Xia
Content may be subject to copyright.
Schematic of proposed mechanism of myocardial ischaemic postconditioning cardioprotection. Ischaemic postconditioning confers cardioprotection through the survivor activating factor enhancement (SAFE) and reperfusion injury salvage kinase (RISK) pathways. These involve the activation of Jak/STAT3 and PI3K/Akt, which subsequently decreases mitochondrial permeability transition pore (mPTP) opening and increases mitochondrial K ATP (Mito K ATP ) channel opening, which attenuates myocardial ischaemia reperfusion injury.
Source publication
Myocardial ischaemia reperfusion injury is the leading cause of death in patients with cardiovascular disease. Interventions such as ischaemic pre and postconditioning protect against myocardial ischaemia reperfusion injury. Certain anaesthesia drugs and opioids can produce the same effects, which led to an initial flurry of excitement given the ex...
Contexts in source publication
Context 1
... cardiomyocyte survival. 14 As the experimental design of IPo mimics IPC and their cardi- oprotective effects are similar, it is not surprising that IPo and IPC share related cardioprotective signalling pathways. Indeed, ele- ments of the RISK pathway, including PI3K, Akt, eNOS, and ad- enosine receptors have also been shown to be involved in IPo (Fig. 3). In isolated rat hearts, IPo stimulation reduced post-is- chaemic infarct size with associated elevations in Akt, eNOS, and p70S6K, while these beneficial effects of IPo were abolished by PI3K inhibition (either by LY294002 or wortmannin), indicating the involvement of PI3K-Akt in IPo. 89 In addition, pharmacologic- al inhibition of ...
Context 2
... factor that has been shown to be an essen- tial component of the SAFE pathway in IPo. Once phosphorylated/ activated, tyrosine-phosphorylated STAT3 shuttles into the nucleus and initiates stress-responsive gene transcription, 96 97 serine-phosphorylated STAT3 moves to mitochondria to regulate the mitochondrial respiratory chain 97 98 (Fig. 3). The importance of STAT3 activation in the context of IPo has been demonstrated by both pharmacological inhibition 99 and genetic deletion of STAT3. 100 However, information regarding how IPo activates STAT3 is lacking. Moreover, although STAT3 is recognized as a tran- scription factor, its activation during myocardial IRI is much too ...
Similar publications
Ischaemic postconditioning (IPostC) was introduced for the first time by Zhao et al. as a feasible method for reduction of myocardial ischaemia–reperfusion (IR) injury. The cardioprotection by this protocol has been extensively evaluated in various species. Then, further research revealed that IPostC is a safe and convenient approach in limiting IR...
Many patients with ischaemic heart disease also have diabetes. As myocardial infarction is a major cause of mortality and morbidity in these patients, treatments that increase cell survival in response to ischaemia and reperfusion are needed. Exosomes—nano-sized, lipid vesicles released from cells—can protect the hearts of non-diabetic rats. We pre...
Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor beta 1 (TGF-β1) superfamily that reverses age-related cardiac hypertrophy, improves muscle regeneration and angiogenesis, and maintains progenitor cells in injured tissue. Recently, targeted myocardial delivery of the GDF11 gene in aged mice was found to reduce h...
Citations
... When analyzing kidney function (creatinine and KIM-1 mRNA [28]), we found a notable decrease in the groups with pharmacological stimulus, compared to the IRI group. Participation of opioids in protection against surgical models has been extensively studied in organs such as the heart [34] and brain [35]. In kidney transplantation, similar molecules could be involved in the shown protection. ...
Progression to renal damage by ischemia-reperfusion injury (IRI) is the result of the dysregulation of various tissue damage repair mechanisms. Anesthetic preconditioning with opioids has been shown to be beneficial in myocardial IRI models. Our main objective was to analyze the influence of pharmacological preconditioning with opioids in renal function and expression of molecules involved in tissue repair and angiogenesis. Experimental protocol includes male rats with 45 min ischemia occluding the left renal hilum followed by 24 h of reperfusion with or without 60 min preconditioning with morphine/fentanyl. We analyzed serum creatinine and renal KIM-1 expression. We measured circulating and intrarenal VEGF. Immunohistochemistry for HIF-1 and Cathepsin D (CTD) and real-time PCR for angiogenic genes HIF-1α, VEGF, VEGF Receptor 2 (VEGF-R2), CTD, CD31 and IL-6 were performed. These molecules are considered important effectors of tissue repair responses mediated by the development of new blood vessels. We observed a decrease in acute renal injury mediated by pharmacological preconditioning with opioids. Renal function in opioid preconditioning groups was like in the sham control group. Both anesthetics modulated the expression of HIF-1, VEGF, VEGF-R2 and CD31. Preconditioning negatively regulated CTD. Opioid preconditioning decreased injury through modulation of angiogenic molecule expression. These are factors to consider when establishing strategies in pathophysiological and surgical processes.
... Central in the pathogenesis of ischaemic myocardial injury is the depletion of highenergy phosphates and the disturbance of normal intracellular calcium (Ca 2+ ) homeostasis [11,13]. The magnitude of reperfusion injury is dependent on the extent of damage to the mitochondrion, which is in turn proportional to the degree of opening of the mitochondrial permeability transition pore (MPTP), ultimately leading to cardiomyocyte death and subsequent irreversible myocardial injury [14]. During ischaemia, the MPTP remains closed, maintaining mitochondrial integrity. ...
... During ischaemia, the MPTP remains closed, maintaining mitochondrial integrity. Upon reperfusion, the tissue re-oxygenation triggers the release of reactive oxygen species (ROS) and the MPTP opens, leading to the disturbance of electrochemical gradients over the mitochondrial membrane, swelling of the mitochondrial intermembrane space and disruption of the supramolecular complex containing the proton pump, adenosine triphosphate (ATP) synthase, the adenine nucleotide transporter and mitochondrial creatine kinase (CK), which uncouples oxidative phosphorylation, decreases nitric oxide (NO) bioavailability, and disrupts intracellular distribution of Ca 2+ , sodium (Na + ), potassium (K + ) and hydrogen ions [13,14]. If the MPTP opening is minimal, full functional recovery of the mitochondrion may occur. ...
... Similar to ischaemic conditioning, anaesthetic conditioning protects the heart and other organs against IR injury through the survivor activating factor enhancement (SAFE) and reperfusion injury salvage kinase (RISK) pathways, which, subsequently, through mitochondrial-dependent and non-mitochondrial-dependent (nuclear or other) signalling pathways decrease MPTP opening, increase mitochondrial K ATP channel opening, activate adenosine receptors, and inhibit Na+/K+ pump which attenuates IR injury [13,14]. Activation of the endogenous protection programme in the heart results in long term protective/resistance against IR [18]. ...
Recent research has contested the previously accepted paradigm that volatile anaesthetics improve outcomes in cardiac surgery patients when compared to intravenous anaesthesia. In this review we summarise the mechanisms of myocardial ischaemia/reperfusion injury and cardioprotection in cardiac surgery. In addition, we make a comprehensive analysis of evidence comparing outcomes in patients undergoing cardiac surgery under volatile or intravenous anaesthesia, in terms of mortality and morbidity (cardiac, neurological, renal, pulmonary).
... As a conclusion, eplerenone was found not to limit the IRI in human ex vivo tissue, which contrasts with previous animal studies. In another study (Xia et al., 2016), the authors explored this aspect, highlighting the big challenge behind the attempts of translating the progresses made using animal models in the human context. There are various explanations behind this, such as portion dose, the force of the applied ischemic impulse, the type of ischemia and lost / reduced cardioprotection in general co-morbidities (e.g. in diabetes and senescence). ...
This report presents an overview of available and emerging non-animal models in the field of cardiovascular disease (CVD) research. Over 14,000 abstracts published between 2013 and 2019 were scanned for relevant non-animal methods for CVD. From these, 449 publications were identified as candidate methods according to selected inclusion/exclusion criteria. In vitro cell and tissue cultures, human ex vivo and in silico approaches were considered and collated into a catalogue to form a key knowledge source for researchers, educators and national ethics and funding authorities. The study confirmed that cell-based models represent fine-tuned approaches, however most of the time they intrinsically lack in three-dimensional structure, except for the growing, yet specific field of cardiovascular tissue engineered constructs. The ex vivo methods are used to overcome the dimensionality limitation, while maintaining the required experimental accuracy. Nevertheless, most of the analysed ex vivo models use animal or human explanted organs, with the difficulty in maintaining their integrity for a long time. Beyond the purely hemodynamic applications offered by computational fluid-dynamics approaches, the computational methods are used to reproduce complex systems, including tissue/organ electrophysiology and tissue remodelling, potentially enabling personalised medicine approaches. In the future, such methods could replace many animal-based experiments in elucidating disease mechanisms and aiding in therapies development.
... However, this leads to irreversible detrimental effects [205]. A previous study suggests that IRI is the predominant pathological condition in cardiovascular diseases, including IHD [206]. Epidemiological studies have shown that a deficiency of plasma HDL-C is closely related to an increased risk of IHD [207,208]. ...
Cholesterol homeostasis plays a significant role in cardiovascular disease. Previous studies have indicated that ATP-binding cassette transporter A1 (ABCA1) is one of the most important proteins that maintains cholesterol homeostasis. ABCA1 mediates nascent high-density lipoprotein biogenesis. Upon binding with apolipoprotein A-I, ABCA1 facilitates the efflux of excess intracellular cholesterol and phospholipids and controls the rate-limiting step of reverse cholesterol transport. In addition, ABCA1 interacts with the apolipoprotein receptor and suppresses inflammation through a series of signaling pathways. Thus, ABCA1 may prevent cardiovascular disease by inhibiting inflammation and maintaining lipid homeostasis. Several studies have indicated that post-transcriptional modifications play a critical role in the regulation of ABCA1 transportation and plasma membrane localization, which affects its biological function. Meanwhile, carriers of the loss-of-function ABCA1 gene are often accompanied by decreased expression of ABCA1 and an increased risk of cardiovascular diseases. We summarized the ABCA1 transcription regulation mechanism, mutations, post-translational modifications, and their roles in the development of dyslipidemia, atherosclerosis, ischemia/reperfusion, myocardial infarction, and coronary heart disease.
... More specifically, I/RI is associated with numerous detrimental influences, including tissue non-uniform flow and cell necrosis and swelling despite the beneficial effects from I/RI by reversing ischemia [1]. One such form of I/RI, namely myocardial I/ RI (MI/RI), a key factor of incidence, disability, and mortality globally, also represents one of the leading fatality-causing phenomena in patients with cardiovascular diseases, leading to severe suffering of the myocardial tissues following the occurrence of serious myocardial infarction [2,3]. As a complicated pathology, MI/RI is characterized by inadequate oxygen supply and blood flow restoration, leading to irreversible damage to the heart tissue [4]. ...
Myocardial ischemia-reperfusion injury (MIRI) represents a coronary artery disease, accompanied by high morbidity and mortality. Sevoflurane post-conditioning (SPC) is importantly reported in myocardial disease. Accordingly, the current study sought to evaluate the role of Sevo in MI/RI. Firstly, MI/RI models were established and subjected to SPC. Subsequently, pathological injury in the myocardium, myocardial infarction areas, H9c2 cell viability, apoptosis, and levels of creatine kinase-MB (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH) were all measured. Ubiquitin-specific peptidase (22USP22), lysine-specific demethylase 3A (KDM3A), and Yes1 associated transcriptional regulator (YAP1) were down-regulated in H9c2 cells using cell transfection to verify their roles. The interaction between USP22 and KDM3A and between KDM3A and YAP1 was further validated. USP 22, KDM3A, and YAP1 were found to be down-regulated in MI/RI and SPC protected MI/RI rats, as evidenced by up-regulated expressions of USP22, KDM3A, and YAP1, reduced pathological injury in the myocardium, myocardial infarction areas, apoptosis, and levels of CK-MB, cTnI, and LDH, and enhanced H9c2 cell viability; while the protective effects of Sevo were counteracted by silencing of USP22, KDM3A, and SPC upregulated USP22, which stabilized KDM3A protein levels via deubiquitination, and KDM3A inhibited histone 3 lysine 9 di-methylation (H3K9me2) levels in the YAP1 promoter to encourage YAP1 transcription, to reduce MI/RI.
... The damage to mitochondria is accompanied by a massive burst of ROS production during reperfusion, which exceeds the antioxidative capacity of the cells and exerts detrimental effects on cardiomyocytes. 27 In this regard, a reduced antioxidant response associated with the increased level of J Teh Univ Heart Ctr 17 (1) http://jthc.tums.ac.ir January, 2022 pro-oxidants has been observed in patients with acute MI. 28 Although it has not been indicated which compartment of cardiomyocytes is the ultimate end-effector of ischemic preconditioning, some studies have suggested that mitochondria can be considered the main signaling pathway in this process. ...
... Mitochondrial KATP channel (Adenosine triphosphate-sensitive K + channels) opening using ischemic preconditioning may not only inhibit mitochondrial Ca 2+ overload, followed by the excessive generation of ROS, but also attenuate myocardial reperfusion-induced injuries. 27 We have previously shown that the blockage of mitochondrial KATP channels might abolish the protective effects of cardiac preconditioning. 29 In this context, the present study demonstrated that pre-ischemic treatment with KCl significantly attenuated the increased levels of PAB and MDA induced by I/R, suggesting that K might exert cardioprotective effects through the reduced activity of ROS. ...
Background: Acute myocardial infarction is an important cause of morbidity. This study aimed to investigate the effects of the administration of potassium chloride (KCl) on reperfusion-induced injuries in a rat model of myocardial ischemia/reperfusion.
Methods: Thirty-six male Wistar rats, weighing 200 to 250 g, were randomly assigned to 3 experimental groups: control, K1 (10 µg/kg of KCl), and K2 (20 µg/kg of KCl). Twenty minutes before ischemia, a single dose of 10 and 20 µg/kg of KCl was intraperitoneally administered in the K1 and K2 groups, respectively. The coronary artery was occluded for 30 minutes (ischemia); thereafter, it was opened for 60 minutes (reperfusion) to measure hemodynamic parameters and ventricular arrhythmias. Blood sampling was performed after the reperfusion period to determine the serum levels of lactate dehydrogenase, troponin I, creatine kinase (CK)-MB, malondialdehyde, and pro-oxidant-antioxidant balance.
Results: Serological parameters significantly decreased in the potassium groups compared with the control group. In particular, the decline was more pronounced for the serum levels of lactate dehydrogenase (1180.25±69.48 vs 1556.67±77.02 U/L; P=0.011), troponin I (21.98±0.61 vs 28.76±1.65 ng/mL; P=0.020), and pro-oxidant-antioxidant balance (15.51±0.72 vs 20.63±1.42 HK; P=0.041) in the K2 group compared with the K1 group. Moreover, the administration of 20 µg/kg of KCl significantly decreased the incidence of ventricular tachycardias and fibrillations compared with the control group (P=0.002). Additionally, no considerable differences were observed between the control group and the groups with 10 µg/kg and 20 µg/kg of KCl regarding the number of ventricular ectopic beats.
Conclusion: The administration of KCl before ischemia could reduce ventricular arrhythmias and reperfusion-induced injuries by reducing oxidative stress.
... 7 Lactate causes a decrease in intracellular pH and interferes with myofibril function. 27,28 Therefore, glutamine can maintain substrate supply for the Krebs cycle during ischemia. 7,19 It can improve cardiac contractility and CI after CPB ( Figure 6). ...
Purpose:
Myocardial injury due to on-pump coronary artery bypass grafting (CABG) in patients with low ejection fraction (EF) is associated with poor outcomes. This study determines whether intravenous glutamine could protect the myocardium during on-pump CABG in patients with low EF.
Materials and methods:
This was a double-blind, randomized controlled trial to assess glutamine as a myocardial protector during on-pump CABG in patients with left ventricle EF of 31-50%, conducted from January to October 2021. Patients in the glutamine group (n = 30) received 0.5 g/kg of 20% glutamine solution diluted with 0.9% NaCl up to 500 mL in total volume over a period of 24 hours. Patients in the control group (n = 30) received 0.9% NaCl over the same period. The primary outcomes were plasma troponin I and plasma glutamine levels. Secondary outcomes included α-ketoglutarate (α-KG) levels and histopathology scoring of the right atrial appendage tissue, plasma lactate levels, hemodynamic measurement, and morbidity.
Results:
Twenty-nine patients from each group (58 in total) were included in the analysis. Plasma troponin I levels at 6 and 24 hours after cardiopulmonary bypass (CPB) were significantly lower in the glutamine than the control group (mean 3.43 ± 1.51 ng/mL vs mean 4.41 ± 1.89 ng/mL; p = 0.034; median 3.08 ng/mL [min-max: 1.30-6.59] vs median 3.77 ng/mL [min-max: 0.00-36.53]; p = 0.038, respectively). Plasma glutamine levels at 24 hours after CPB were significantly higher in the glutamine than the control group (mean 935.42 ± 319.10 μmol/L vs mean 634.79 ± 243.89 μmol/L, p = 0.001). Plasma lactate levels at 6 and 24 hours after CPB were significantly lower in the glutamine than the control group (median 5.30 mmol/L [min-max: 1.20-9.50] vs median 5.70 mmol/L [min-max: 2.80-11.30], p = 0.042; mean 2.08 ± 0.67 mmol/L vs mean 2.46 ± 0.69 mmol/L, p = 0.044, respectively). Myocardial injury score was significantly lower in the glutamine than the control group (mean 1.30 ± 0.24 vs mean 1.48 ± 0.26, p = 0.011).
Conclusion:
Perioperative administration of 0.5 g/kg intravenous glutamine solution over the period of 24 hours has myocardial protection effect in patients with low EF who undergo elective on-pump CABG.
... Critical roles of NO in myocardial function and vascular tone regulation under physiological conditions made NO the focus of numerous studies concerning cardioprotective therapeutic strategies. Opposing results from different studies examining the role of NO in RIPC-mediated protection against I/R injury can be explained by different NOS isoform involvement and varying experimental conditions-concentration of produced NO, subcellular localization, and its bioavailability [18]. Higher concentrations of NO seem to have detrimental effects on myocardial function, while physiological levels of NO can be protective in preconditioning to I/R injury [19]. ...
Remote ischaemic preconditioning (RIPC) is a medical procedure that consists of repeated brief periods of transient ischaemia and reperfusion of distant organs (limbs) with the ability to provide internal organ protection from ischaemia. Even though RIPC has been successfully applied in patients with myocardial infarction during coronary revascularization (surgery/percutaneous angioplasty), the underlying molecular mechanisms are yet to be clarified. Thus, our study aimed to determine the role of nitric oxide synthase (NOS) isoforms in RIPC-induced protection (3 × 5 min of forearm ischaemia with 5 min of reperfusion) of arterial graft in patients undergoing urgent coronary artery bypass grafting (CABG). We examined RIPC effects on specific expression and immunolocalization of three NOS isoforms — endothelial (eNOS), inducible (iNOS) and neuronal (nNOS) in patients’ internal thoracic artery (ITA) used as a graft. We found that the application of RIPC protocol leads to an increased protein expression of eNOS, which was further confirmed with strong eNOS immunopositivity, especially in the endothelium and smooth muscle cells of ITA. The same analysis of two other NOS isoforms, iNOS and nNOS, showed no significant differences between patients undergoing CABG with or without RIPC. Our results demonstrate RIPC-induced upregulation of eNOS in human ITA, pointing to its significance in achieving protective phenotype on a systemic level with important implications for graft patency.
... The narrow QRS complex depicted ventricular depolarization or quicker cardiac ejection. However, prolongation in QRS interval represents delayed ventricular depolarization, suggesting the inability of cardiac tissue towards the ejection, which may be due to tissue ischemia or infarction [64]. Thus, ECG findings have been suggested as an important prognostic and non-invasive tool for quicker diagnosing ischemic heart disease [52]. ...
Myocardial ischemia-reperfusion injury (IRI) is one of the most leading concerns for public health globally. Diazepam, a local anesthetic, has been reported for its cardioprotective potential. The present investigation aimed to evaluate the possible mechanism of action of diazepam against left anterior descending ligation-induced myocardial IRI in experimental rats. IRI was induced in healthy male rats by ligating coronary artery for 30 min and then reperfused for 60 min. The animals were pre-treated with either vehicle or diltiazem (10 mg/kg) or diazepam (1, 2.5, and 5 mg/kg) for 14 days. Compared to the IRI group, diazepam (2.5 and 5 mg/kg) markedly (P<0.05) attenuated IRI-induced alterations in cardiac function and oxido-nitrosative stress. In addition, diazepam prominently (P<0.05) improved cardiac Na+K+ATPase, Ca2+ATPase levels and HIF-1α (Hypoxia-Inducible Factor-1 alpha) mRNA expression. It also significantly (P<0.05) down-regulated cardiac mRNA expressions of cTn-I (cardiac troponin I), CCR2 (C-C chemokine receptor type 2), TNF-α (Tumor necrosis factor-alpha), IL (Interleukins)-1β, and IL-6. In western blot analysis, IRI-induced myocardial apoptosis was reduced by diazepam treatment reflected by a marked (P<0.05) decreased in Bax (Bcl-2-associated X protein) and Caspase-3 protein expression. Diazepam also efficiently (P<0.05) improved IRI-induced histological aberration in cardiac tissue. In conclusion, diazepam exerts cardioprotective effect by inhibiting inflammatory release (CCR2, TNF-α, and ILs), oxido-nitrosative stress, and apoptosis (Bax and Caspase-3) pathway during myocardial IRI in experimental rats.
... Given the obvious clinical implications, intense research has been conducted to dissect the potential mechanisms underlying the cardioprotection conferred by preconditioning. In addition to ischemia, preconditioning with mechanical stretch, heat stress, metabolic challenge, and pharmacological agents can induce protective effects [11][12][13]. Recently, Wei et al. reported that retraction of short-term pressure overload increases the resistance of the heart to the development of pathological hypertrophy in a process termed hypertrophic preconditioning [14]. ...
Ischemic preconditioning induced by brief periods of coronary occlusion and reperfusion protects the heart from a subsequent prolonged ischemic insult. In this study we investigated whether a short-term nonischemic stimulation of hypertrophy renders the heart resistant to subsequent ischemic injury. Male mice were subjected to transient transverse aortic constriction (TAC) for 3 days followed aortic debanding on D4 (T3D4), as well as ligation of the left coronary artery to induce myocardial infarction (MI). The TAC preconditioning mice showed markedly improved contractile function and significantly reduced myocardial fibrotic area and apoptosis following MI. We revealed that TAC preconditioning significantly reduced MI-induced oxidative stress, evidenced by increased NADPH/NADP ratio and GSH/GSSG ratio, as well as decreased mitochondrial ROS production. Furthermore, TAC preconditioning significantly increased the expression and activity of SIRT3 protein following MI. Cardiac-specific overexpression of SIRT3 gene through in vivo AAV-SIRT3 transfection partially mimicked the protective effects of TAC preconditioning, whereas genetic ablation of SIRT3 in mice blocked the protective effects of TAC preconditioning. Moreover, expression of an IDH2 mutant mimicking deacetylation (IDH2 K413R) in cardiomyocytes promoted myocardial IDH2 activation, quenched mitochondrial reactive oxygen species (ROS), and alleviated post-MI injury, whereas expression of an acetylation mimic (IDH2 K413Q) in cardiomyocytes inactivated IDH2, exacerbated mitochondrial ROS overload, and aggravated post-MI injury. In conclusion, this study identifies TAC preconditioning as a novel strategy for induction of an endogenous self-defensive and cardioprotective mechanism against cardiac injury. Therapeutic strategies targeting IDH2 are promising treatment approaches for cardiac ischemic injury.
