Inhibition of Cardiac GCH1 O-GlcNAc Modification promotes cardiac BH4/eNOS signaling after myocardial ischemia-reperfusion in mice with Type-2 Diabetes

Abstract

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.