Diabetic cardiomyopathy (DCM) is the primary cause of morbidity and mortality in diabetic cardiovascular complications, which initially manifests as cardiac hypertrophy, myocardial fibrosis, dysfunctional remodeling, and diastolic dysfunction, followed by systolic dysfunction, and eventually end with acute heart failure. Molecular mechanisms underlying these pathological changes in diabetic hearts are complicated and multifactorial, including but not limited to insulin resistance, oxidative stress, lipotoxicity, cardiomyocytes apoptosis or autophagy, inflammatory response, and myocardial metabolic dysfunction. With the development of molecular biology technology, accumulating evidence illustrates that members of the class O of Forkhead box (FoxO) transcription factors are vital for maintaining cardiomyocyte metabolism and cell survival, and the functions of the FoxO family proteins can be modulated by a wide variety of post-translational modifications including phosphorylation, acetylation, ubiquitination, arginine methylation, and O-glycosylation. In this review, we highlight and summarize the most recent advances in two members of the FoxO family (predominately FoxO1 and FoxO3a) that are abundantly expressed in cardiac tissue and whose levels of gene and protein expressions change as DCM progresses, with the goal of providing valuable insights into the pathogenesis of diabetic cardiovascular complications and discussing their therapeutic potential and possible effects of salvianolic acids, a natural product.

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.