Abstract
Introduction: Ischemic preconditioning (IPC) is an intrinsic protective mechanism which markedly enhanced the ability of the heart to withstand a subsequent ischemic injury. We previously found that IPC cardioprotection was markedly attenuated in diabetic rats. Therefore, we hypothesized that insulin-regulated myocardial substrate metabolism may play a key role in IPC-afforded cardioprotection. Methods: Adult male rats were subjected to 30 min of myocardial ischemia and 3 h of reperfusion (MI/R). IPC was achieved by two cycles of 5 min ischemia and 5 min reperfusion. Myocardial glucose and fatty acid (FA) uptake were assessed at the end of 1 h reperfusion by determining 18 F-2-deoxy-2-fluoro-D-glucose uptake and fatty acid translocase (FAT)/CD36 translocation, respectively. Results: IPC significantly improved cardiac function (n=8, P <0.05) with reduced myocardial infarction, apoptotic cell death and blood creatine kinase/lactate dehydrogenase levels following MI/R (all P <0.05). Myocardial glucose uptake was markedly elevated after IPC treatment (17.0±1.5 vs. 12.4±1.0 in MI/R, n=10-12, P <0.05), as well as translocation of glucose transporter 4 (GLUT4) to plasma membrane (PM) ( P <0.01). Meanwhile, myocardial PI3K expression and Akt phosphorylation were significantly enhanced in IPC group ( P <0.05). Interestingly, IPC also increased CD36 translocation to PM and AMPK phosphorylation ( P <0.05). Wortmannin not only abrogated the cardioprotective effect of IPC, but also inhibited IPC-induced Akt/AMPK phosphorylation and subsequent GLUT4/CD36 translocation. Furthermore, the cardioprotection of IPC was markedly blunted in STZ-induced insulin-deficient diabetic hearts with failure of increase in glucose/FA uptake and impaired IPC-stimulated PI3K-Akt and AMPK signaling (n=6, P <0.05). Conclusions: These results suggest that IPC increases both glucose and FA uptake during early reperfusion to resist myocardial injury via insulin-stimulated, and PI3K-dependent Akt and AMPK activation. Therefore, augmenting insulin signaling may be a potential therapy to improve myocardial substrate uptake and restore the cardioprotection of IPC in diabetic hearts.
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