AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury.
AMPK-regulated and Akt-dependent enhancement of glucose uptake is essential in ischemic preconditioning-alleviated reperfusion injury.
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AMPK 调节和 Akt 依赖性的葡萄糖摄取增强对于缺血预处理减轻再灌注损伤至关重要
DOI：
10.1371/journal.pone.0069910
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Gao F
中科院分区：
文献类型：
--
作者：
Ji L;Zhang X;Liu W;Huang Q;Yang W;Fu F;Ma H;Su H;Wang H;Wang J;Zhang H;Gao F
目的缺血预处理（IPC）是一种有效的内源性保护机制。然而，IPC诱导的心脏保护作用在胰岛素抵抗相关疾病中明显减弱，其机制尚不清楚。本研究旨在确定葡萄糖代谢在IPC减少的再灌注损伤中的作用。方法正常或链脲佐菌素（STZ）治疗的糖尿病大鼠在心肌缺血（30 min）/再灌注（3 h）前进行2个周期的5 min缺血/5 min再灌注。心肌葡萄糖摄取通过18F-氟脱氧葡萄糖-正电子发射断层扫描（PET）和γ计数器生物分布测定。结果IPC对缺血再灌注大鼠心肌有明显的保护作用，并能显著增加再灌注后1h心肌葡萄糖摄取（P<0.01）。同时，心肌葡萄糖转运蛋白4（GLUT 4）向质膜的转位以及心肌Akt和AMPK磷酸化在预处理心脏中显著增强。心肌内注射GLUT 4 siRNA显著降低GLUT 4表达，并通过增加心肌梗死面积来阻断IPC的心脏保护作用。此外，PI 3 K抑制剂wortmannin显著抑制Akt和AMPK的激活，减少GLUT 4易位，葡萄糖摄取，并最终抑制IPC诱导的心脏保护作用。此外，IPC提供的抗凋亡作用显着钝化STZ治疗的糖尿病大鼠。外源性胰岛素可通过激活AMPK和Akt来改善心肌葡萄糖摄取，减轻心肌缺血再灌注损伤（P<0.05）。结论本研究首次在体内应用直接基因调控技术研究了缺血预处理再灌注过程中心肌葡萄糖代谢的作用。IPC减轻再灌注损伤的关键是通过AMPK和Akt的共同激活增加再灌注心肌的葡萄糖摄取。这种内在的代谢调节和心脏保护能力存在于STZ治疗的心脏中，并且可以由胰岛素触发。
Aims 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 18F-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.
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影响因子：
6.5
作者：
Pu, Jing;Peng, Gong;Liu, Pingsheng
通讯作者：
Liu, Pingsheng
影响因子：
10.8
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Doenst, T
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