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Experimental research
Increased myocardial substrate uptake contributes to the protection of ischemic preconditioning: role of insulin-dependent Akt and AMPK activation
  1. Ji Lele1,
  2. Liu Wenchong1,
  3. Fu Feng1,
  4. Yang Weidong2,
  5. Wang Jing2,
  6. Zhang Haifeng1,
  7. Gao Feng1
  1. 1Department Of Physiology, Fourth Military Medical University, Xi'an, China
  2. 2Department Of Nuclear Medicine, Xijing Hospital, Fourth Military Medical University, Xi'an, China

Abstract

Introduction Switched myocardial substrate uptake from fatty acids to carbohydrate has been proposed to resist ischemia/reperfusion injury. We hypothesised that altered myocardial substrate uptake during early reperfusion may contribute to 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 fluorodeoxyglucose uptake and fatty acid translocase (FAT)/CD36 translocation, respectively.

Results IPC significantly improved cardiac functions, reduced myocardial infarction, apoptotic cell death and blood CK/LDH 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 group, p<0.05, n=10-12), 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 (both 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 signalling (p<0.05, n=6).

Conclusions IPC increased both glucose and FA uptake during early reperfusion to resist myocardial injury via insulin/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 the diabetic hearts.

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