Abstract 14404: O-GlcNAc Mediates Cardioprotection by Remote Ischemic Preconditioning and Induces a State of Chronic Cardioprotection in Diabetes Mellitus
Posttranslational modification of proteins by O-linked β-N-acetylglucosamine (O-GlcNAc) is cardioprotective but its role in cardioprotection by remote ischemic preconditioning (rIPC) and the reduced efficacy of rIPC in type 2 diabetes mellitus is unknown
Hypothesis: The remote stimulus mediating and the target organ response eliciting the cardioprotective effect of rIPC in non-diabetic and diabetic myocardium activates O-GlcNAcylation.
Methods and Results: The cardioprotective capacity and influence on myocardial O-GlcNAc levels of plasma dialysate from 8 healthy volunteers and 8 type 2 diabetic patients drawn before and after rIPC, were tested on human isolated atrial trabeculae subjected to ischemia-reperfusion injury. Dialysate from healthy volunteers exposed to rIPC improved post ischemic hemodynamic recovery (40±6% vs 16±2%; p<0.01) and increased myocardial O-GlcNAc levels (Figure 1a, left columns). Similar observations were made with dialysate from diabetic patients before exposure to rIPC (43±3% vs 16±2%; p<0.001) but no additional cardioprotection or further increase of O-GlcNAc levels was achieved by perfusion with dialysate after exposure to rIPC (Figure 1a, right columns). Also diabetic atrial tissue displayed improved hemodynamic recovery and increased O-GlcNAc levels when perfused with control dialysate (Figure 1b). No additional cardioprotection was conferred by rIPC. The GFAT inhibitor azaserine abolished the cardioprotective effects and the increment in myocardial O-GlcNAc levels afforded by rIPC and diabetes.
Conclusions: rIPC and diabetes per se increase myocardial O-GlcNAc levels through circulating humoral factors. O-GlcNAc signaling participates in mediating rIPC induced cardioprotection and maintaining a state of inherent chronic activation of cardioprotection in diabetic myocardium, restricting it from further protection by rIPC.
- © 2012 by American Heart Association, Inc.