Department of Physiology, Fourth Military Medical University, Xi'an, China.
PLoS One. 2013 Jul 26;8(7):e69910. doi: 10.1371/journal.pone.0069910. Print 2013.
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.
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.
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).
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.
缺血预处理（IPC）是一种有效的内源性保护形式。然而，在与胰岛素抵抗相关的疾病中，IPC 诱导的心脏保护作用显著减弱，其潜在机制尚不清楚。本研究旨在确定葡萄糖代谢在 IPC 减轻再灌注损伤中的作用。
正常或链脲佐菌素（STZ）处理的糖尿病大鼠在心肌缺血（30 分钟）/再灌注（3 小时）前进行 2 个周期的 5 分钟缺血/5 分钟再灌注。通过（18）F-氟脱氧葡萄糖正电子发射断层扫描（PET）扫描和伽马计数器生物分布测定来确定心肌葡萄糖摄取。
IPC 发挥了显著的心脏保护作用，并在再灌注后 1 小时明显改善了心肌葡萄糖摄取（P<0.01），这在缺血/再灌注大鼠的 PET 图像和伽马计数器生物分布测定中得到了证实。同时，在预处理的心脏中，葡萄糖转运蛋白 4（GLUT4）向质膜的转移以及心肌 Akt 和 AMPK 磷酸化明显增强。心肌内注射 GLUT4 siRNA 显著降低 GLUT4 表达，并阻断 IPC 的心脏保护作用，表现为心肌梗死面积增加。此外，PI3K 抑制剂wortmannin 显著抑制 Akt 和 AMPK 的激活，减少 GLUT4 转位、葡萄糖摄取，并最终抑制 IPC 诱导的心脏保护作用。此外，IPC 提供的抗凋亡作用在 STZ 处理的糖尿病大鼠中明显减弱。外源性胰岛素补充通过心肌 AMPK 和 Akt 的共同激活显著改善了葡萄糖摄取，并减轻了缺血/再灌注损伤，这表现在 STZ 处理的大鼠中，心肌凋亡和梗死面积减少（P<0.05）。
本研究首次使用体内直接遗传调节，研究了再灌注期间心肌葡萄糖代谢在 IPC 中的作用。在再灌注心肌中，通过心肌 AMPK 和 Akt 的共同激活增加葡萄糖摄取，对于 IPC 减轻再灌注损伤是必要的。这种内在的代谢调节和心脏保护能力存在于 STZ 处理的心脏中，并可以被胰岛素触发。
