Myocardial infarction is one of the primary causes of mortality in patients with coronary heart disease worldwide. Early treatment of acute myocardial infarction restores blood supply of ischemic myocardium and decreases the mortality risk. However, when the interrupted myocardial blood supply is recovered within a certain period of time, it causes more serious damage to the original ischemic myocardium; this is known as myocardial ischemia/reperfusion injury (MIRI). The pathophysiological mechanisms leading to MIRI are associated with oxidative stress, intracellular calcium overload, energy metabolism disorder, apoptosis, endoplasmic reticulum stress, autophagy, pyroptosis, necroptosis and ferroptosis. These interplay with one another and directly or indirectly lead to aggravation of the effect. In the past, apoptosis and autophagy have attracted more attention but necroptosis and ferroptosis also serve key roles. However, the mechanism of MIRI has not been fully elucidated. The present study reviews the mechanisms underlying MIRI. Based on current understanding of the pathophysiological mechanisms of MIRI, the association between cell death-associated signaling pathways were elaborated, providing direction for investigation of novel targets in clinical treatment.
ID 22693 Poster Board 361Reperfusion after myocardial infarction may further increase myocardial injury, which can be exacerbated by diabetes. Strategies have been developed to ameliorate myocardial ischemia/reperfusion injuries (MIRI) yet the effectiveness of these strategies mostly diminish in diabetes largely due to diminished nitric oxide bioavailability in the cardiovascular system. GTP cyclohydrolase 1 (GCH1) and its product tetrahydrobiopterin (BH4), a co-factor of the endothelial nitric oxide synthase (eNOS), play crucial roles in cardiovascular physiology and in MIRI. O-GlcNAcylation is a ubiquitous post-translational modification that is extremely labile and plays a significant role in physiology, especially in the heart. Sustained activation of cardiac O-GlcNAcylation leads to detrimental effects on cardiovascular function. However, transient elevation of some cardiac protein O-GlcNAcylation can exert beneficial effects in the heart. When chronic diabetes meets acute ischemic injury, the role and regulation of O-GlcNAcylation and in particular its impact on cardiac GCH1 are enigmatic. Here we report that hyper-O-GlcNAc modification of GCH1 may impair its enzymatic activity and subsequently lose its cardioprotective effects against MIRI in mice with type 2 diabetes.
Subjects with diabetes are more vulnerable to myocardial ischemic-reperfusion injury (MIRI) and less or not sensitive to myocardial protective interventions such as ischemic preconditioning that are otherwise effective in non-diabetic subjects, and the underlying mechanism is unclear. Propofol (PPF), a widely used intravenous anesthetics, has been reported to attenuate MIRI through its reactive oxygen species scavenging property at high doses in vitro and in vivo, while application of propofol at high doses clinically may cause hemodynamic instability. Salvianolic acid A(SAA) is a potent antioxidant that confers protection against myocardial ischemic injuries. PPF and SAA both bear phenolic moieties in their molecular structure, however, whether or not these two molecules may confer synergistic cardioprotection, in particular in the context of myocardial ischemic injury under diabetic conditions, is unknown. The aim of this study was to investigate the protective effects and its underlying mechanisms of low doses of PPF combined with SAA against hypoxia/reoxygenation(H/R)-induced cardiomyocyte injury in high glucose (HG) and palmitate-treated H9c2 cardiomyocytes. Our data showed that culture H9c2 cells under stimulated diabetic condition with HG and palmitate resulted in significant cellular injury evidenced as decreased cell viability and increased lactate dehydrogenase (LDH) leakage that was concomitant with increased levels of the lipid peroxidation product malondialdehyde(MDA) and significant increase in CD36, while levels of p-AMPK was significantly reduced. These HG and palmitate-induced cell injuries/damages were further significantly exacerbated by H/R (composed of 6 hours of hypoxia followed by 12 hours of reoxygenation) but reversed by PPF or SAA respectively in a concentration dependent manner in the dose ranges of 12.5, 25 and 50 mM. Co-administration of low concentrations of PPF and SAA at 12.5 mM in H9c2 cells cultured under HG and palmitate significantly reduced the production of reactive oxygen species, ferrous ion content and lipid peroxidation and reduced CD36, while significantly increased p-AMPK, as compared to the effects of PPF at the concentration of 25 mM. Moreover, HR-induced cellular injuries and ferroptosis were significantly exacerbated by overexpression of CD36. It is concluded that combinational usage of low doses/concentrations of PPF and SAA confer superior cellular protective effects to the use of high dose of PPF alone, and that inhibition of H/R induced CD36 over-expression may represent a major mechanism by which PPF and SAA combat against cardiomyocyte H/R injuries under HG and high lipid conditions.
Background Patients with diabetes are more vulnerable to myocardial ischemia/reperfusion injury (MIRI). Abnormal increases of cardiac Connexin43 (Cx43) were shown to be associated with a variety of pathological conditions including myocardial ischemia and diabetic cardiomyopathy, concomitant with various degrees of changes in autophagy. However, the role of Cx43 in MIRI in diabetic conditions and in particular its potential interplay with cardiac autophagy in this pathology is unknown. Thus, the present study was aimed to explore the role and mechanism of Cx43 in diabetic MIRI. Methods and Results Streptozotocin (STZ)‐induced diabetic and age‐matched control rats were subjected to MIRI by occluding the left coronary artery for 30 minutes followed by 2 hours of reperfusion at 5 weeks of diabetes induction. In vitro, rat origin H9C2 cardiomyocytes (H9C2) were exposed to 35mmol/L high glucose(HG)for 48 hours(h) in the absence or presence of Cx43 gene knockdown with siRNA, followed by hypoxia for 6h and reoxygenation for 12h. Myocardial infarct size was assessed by TTC staining. Cell viability was detected by the CCK‐8 assay, apoptosis by TUNEL assay. Cardiac Cx43 protein, apoptosis‐related proteins and autophagy‐related LC3, p62 and mTOR proteins were assessed by Western blotting. Post‐ischemic myocardial infarct size and cardiac CX43 protein expression were significantly increased in diabetic rats as compared with that in the control (p<0.05), concomitant with increases in the ratio of LC3 II/I and in the protein expression of P62 and mTOR (all p<0.05). In vitro, exposure of H9C2 cells to HG significantly increased cell injury evidenced by increased LDH release and reduced cell viability, and significantly enhanced cell apoptosis and reactive oxygen species(ROS) production that was accompanied by increased cardiomyocyte CX43 overexpression and enhanced autophagy but paradoxically also enhanced mTOR activation, similar to that seen in vivo. All these changes were further exacerbated following H/R under HG. Cx43 Knockdown in H9C2 results in decreased ROS production and decreased apoptosis after H/R under HG leading to increased cell viability (all p<0.05), while Cx43 knockdown attenuated autophagy. Application of the selective mTOR inhibitor rapamycin abolished the abovementioned beneficial effects of Cx43 Knockdown. Conclusion Overexpressed CX43 in the diabetic heart exacerbates MIRI in diabetes through enhanced cardiac autophagy under hyperglycemic condition.
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