AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury.
OBJECTIVE
Ischemic 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.


METHODS
Normal 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 (18)F-fluorodeoxyglucose-positron emission tomography (PET) scan and gamma-counter biodistribution assay.


RESULTS
IPC 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).


CONCLUSIONS
The 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.
Department of Physiology, Fourth Military Medical University, Xi'an, China.
Lele
L
Ji
Xing
X
Zhang
Wenchong
W
Liu
Qichao
Q
Huang
Weidong
W
Yang
Feng
F
Fu
Heng
H
Ma
Hui
H
Su
Haichang
H
Wang
Jing
J
Wang
Haifeng
H
Zhang
Feng
F
Gao
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000201:enzymology / Q000503:physiopathology; D004789:Enzyme Activation / Q000187:drug effects; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006334:Heart Function Tests; D007328:Insulin / Q000494:pharmacology; D019157:Ischemic Preconditioning, Myocardial; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D000077191:Wortmannin
D000730:Androstadienes; D002316:Cardiotonic Agents; D051275:Glucose Transporter Type 4; D007328:Insulin; D034741:RNA, Small Interfering; C495694:Slc2a4 protein, rat; D013311:Streptozocin; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000077191:Wortmannin