%0 Journal Article
%T Acute Hyperglycemia Abolishes Ischemic Preconditioning by Inhibiting Akt Phosphorylation: Normalizing Blood Glucose before Ischemia Restores Ischemic Preconditioning
%A Zequan Yang
%A Yikui Tian
%A Yuan Liu
%A Sara Hennessy
%A Irving L. Kron
%A Brent A. French
%J Oxidative Medicine and Cellular Longevity
%D 2013
%I Hindawi Publishing Corporation
%R 10.1155/2013/329183
%X This study examined the hypothesis that acute hyperglycemia (HG) blocks ischemic preconditioning (IPC) by inhibiting Akt phosphorylation. Brief HG of approximately 400£¿mg/dL was induced in C57BL/6 mice via intraperitoneal injection of 20% dextrose (2£¿g/kg). All mice underwent 40£¿min LAD occlusion and 60£¿min reperfusion. The IPC protocol was 2 cycles of 5£¿min ischemia and 5£¿min reperfusion prior to index ischemia. Results. In control mice, infarct size (IF) was 51.7 ¡À 2.0 (% risk region). Preconditioning reduced IF by 50% to 25.8 ¡À 3.2 ( versus control). In HG mice, IF was significantly exacerbated to 58.1 ¡À 2.3. However, the effect of IPC completely disappeared in HG mice. Normalization of blood glucose with insulin 5 min before IPC recovered the cardioprotective effect. Administration of CCPA before index ischemia mimicked IPC effect. The cardioprotective effect of CCPA, not its chronotropic effect, completely disappeared in HG mice. Phosphorylation of cardiac tissue Akt before index ischemia was enhanced by IPC or CCPA but was significantly inhibited by HG in both groups. Normalization of glucose with insulin reversed the inhibition of Akt phosphorylation by HG. Conclusion. HG abolishes the cardioprotective effect of preconditioning by inhibiting Akt phosphorylation. Normalization of blood glucose with insulin suffices to recover the cardioprotective effect of preconditioning. 1. Introduction Hyperglycemia is commonly present in the perioperative period in patients undergoing cardiac surgery [1¨C3]. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality and morbidity in both diabetic and nondiabetic patients [3]. An increasing body of clinical evidence has shown that acute hyperglycemia (or stress hyperglycemia) is independently associated with larger myocardial infarct (MI) size and impaired left ventricular function in both diabetic and nondiabetic patients [4¨C6]. Animal studies have also shown that the size of MI increases in response to elevations in blood glucose levels [7, 8]. Ischemic preconditioning is a powerful endogenous protective mechanism against myocardial ischemia/reperfusion injury, which is induced by brief episodes of ischemia and reperfusion before the prolonged index myocardial ischemia and reperfusion [9]. However, diabetes mellitus and acute hyperglycemia have been shown to counteract the cardioprotective effects of both ischemic and pharmacological preconditioning in animals and humans [7, 10¨C12]. The mechanisms underlying the hyperglycemic blockade of preconditioning remain to be defined.
%U http://www.hindawi.com/journals/omcl/2013/329183/