AMPK-Regulated and Akt-Dependent Enhancement of Glucose Uptake Is Essential in Ischemic Preconditioning-Alleviated Reperfusion Injury

Abstract

AimsIschemic preconditioning (IPC) is a potent form of endogenous protection. However, IPC-induced cardioprotective effect is significantly blunted in insulin resistance-related diseases and the underlying mechanism is unclear. This study aimed to determine the role of glucose metabolism in IPC-reduced reperfusion injury.MethodsNormal or streptozotocin (STZ)-treated diabetic rats subjected to 2 cycles of 5 min ischemia/5 min reperfusion prior to myocardial ischemia (30 min)/reperfusion (3 h). Myocardial glucose uptake was determined by 18F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay.ResultsIPC exerted significant cardioprotection and markedly improved myocardial glucose uptake 1 h after reperfusion (P<0.01) as evidenced by PET images and gamma-counter biodistribution assay in ischemia/reperfused rats. Meanwhile, myocardial translocation of glucose transporter 4 (GLUT4) to plasma membrane together with myocardial Akt and AMPK phosphorylation were significantly enhanced in preconditioned hearts. Intramyocardial injection of GLUT4 siRNA markedly decreased GLUT4 expression and blocked the cardioprotection of IPC as evidence by increased myocardial infarct size. Moreover, the PI3K inhibitor wortmannin significantly inhibited activation of Akt and AMPK, reduced GLUT4 translocation, glucose uptake and ultimately, depressed IPC-induced cardioprotection. Furthermore, IPC-afforded antiapoptotic effect was markedly blunted in STZ-treated diabetic rats. Exogenous insulin supplementation significantly improved glucose uptake via co-activation of myocardial AMPK and Akt and alleviated ischemia/reperfusion injury as evidenced by reduced myocardial apoptosis and infarction size in STZ-treated rats (P<0.05).ConclusionsThe present study firstly examined the role of myocardial glucose metabolism during reperfusion in IPC using direct genetic modulation in vivo. Augmented glucose uptake via co-activation of myocardial AMPK and Akt in reperfused myocardium is essential to IPC-alleviated reperfusion injury. This intrinsic metabolic modulation and cardioprotective capacity are present in STZ-treated hearts and can be triggered by insulin.

A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake

“…The potentiation effect of A-769662 only involves the AMPK catalytic ␣ 2 -subunit, in agreement with evidence showing that LKB1/AMPK␣ 2 are particularly important for the regulation of cardiac metabolism under ischemia or ischemia-mimetic treatments (8,19,45). Glucose uptake is required to produce ATP via anaerobic glycolysis and is essential to decrease ischemia-reperfusion injury (21). Therefore, its overstimulation certainly participates in the protective action of A-769662 in hypoxia/ ischemia.…”

Molecular Basis of Cardioprotection

“…254 Transgenic overexpression of protein H 11 kinase results in largely reduced IS, along with activation of Akt. 255 AMP-activated protein kinase is activated by IPC and associated with sarcolemmal K ATP activation and action potential duration shortening, 256 and AMP-activated protein kinase activation contributes to glucose transporter 4 upregulation, improved glucose uptake, reduced IS in acute IPC, 257 and attenuation of stunning in late IPC.…”

Experimental Diabetes Mellitus in Different Animal Models

“…Similarly, a study by Ji et al proved that diabetes impaired preconditioning [81]. Ischemic preconditioning was abolished in STZ-treated rats due to a failure to increase glucose uptake during reperfusion [81].…”

“…Similarly, a study by Ji et al proved that diabetes impaired preconditioning [81]. Ischemic preconditioning was abolished in STZ-treated rats due to a failure to increase glucose uptake during reperfusion [81]. It was shown by Vinokur et al that impaired iron homeostasis in diabetic heart can lead to failure of preconditioning to induce myocardial protection [82].…”