Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation
Deficiency in AMPK attenuates ethanol-induced cardiac contractile dysfunction through inhibition of autophagosome formation
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DOI：
10.1093/cvr/cvs127
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发表时间：
2012-06-01
影响因子：
10.8
通讯作者：
Ren, Jun
中科院分区：
文献类型：
--
作者：
Guo, Rui;Ren, Jun
酗酒通常会触发心肌收缩功能受损，同时激活amp激活的蛋白激酶（AMPK）。考虑到AMPK通过哺乳动物雷帕霉素复合物1 （mTORC1）和unc51样激酶（ULK1）在自噬启动中的作用，本研究旨在研究AMPK缺乏对心功能的影响，以及急性乙醇刺激后自噬的机制。过度表达AMPK激酶死亡（KD） 2亚型（K45R突变）的野生型（WT）和转基因小鼠用乙醇刺激。葡萄糖耐量、超声心动图、兰根多夫心脏和心肌细胞收缩功能、自噬和自噬信号包括AMPK、乙酰辅酶a羧化酶（ACC）、mTOR、mtorc1相关蛋白Raptor和ULK1进行了检测。乙醇暴露引发葡萄糖耐受不良和心脏收缩受损，并伴有AMPK和ACC磷酸化增加以及自噬体积累（LC3II和p62增加），其影响因AMPK缺乏或抑制而减弱或减轻。乙醇分别抑制和刺激mTOR和Raptor的磷酸化，其作用被AMPK缺乏所消除。ULK1的Ser（757）和Ser（777）磷酸化分别被乙醇下调和上调，其作用被AMPK缺乏或抑制抵消。此外，乙醇刺激可增强H9c2细胞的LC3点，促进心肌收缩功能障碍，这些作用可通过抑制自噬或AMPK来消除。溶酶体抑制未能加重乙醇诱导的LC3II和p62的升高。综上所述，这些数据表明乙醇暴露可能通过ampk - mtorc1 - ulk1介导的自噬相关机制触发心肌功能障碍。
Binge drinking often triggers compromised myocardial contractile function while activating AMP-activated protein kinase (AMPK). Given the role of AMPK in the initiation of autophagy through the mammalian target of rapamycin complex 1 (mTORC1) and Unc51-like kinase (ULK1), this study was designed to examine the impact of AMPK deficiency on cardiac function and the mechanism involved with a focus on autophagy following an acute ethanol challenge.Wild-type (WT) and transgenic mice overexpressing a kinase-dead (KD) 2 isoform (K45R mutation) of AMPK were challenged with ethanol. Glucose tolerance, echocardiography, Langendorff heart and cardiomyocyte contractile function, autophagy, and autophagic signalling including AMPK, acetyl-CoA carboxylase (ACC), mTOR, the mTORC1-associated protein Raptor, and ULK1 were examined. Ethanol exposure triggered glucose intolerance and compromised cardiac contraction accompanied by increased phosphorylation of AMPK and ACC as well as autophagosome accumulation (increased LC3II and p62), the effects of which were attenuated or mitigated by AMPK deficiency or inhibition. Ethanol dampened and stimulated, respectively, the phosphorylation of mTOR and Raptor, the effects of which were abolished by AMPK deficiency. ULK1 phosphorylation at Ser(757) and Ser(777) was down-regulated and up-regulated, respectively, by ethanol, the effect of which was nullified by AMPK deficiency or inhibition. Moreover, the ethanol challenge enhanced LC3 puncta in H9c2 cells and promoted cardiac contractile dysfunction, and these effects were ablated by the inhibition of autophagy or AMPK. Lysosomal inhibition failed to accentuate ethanol-induced increases in LC3II and p62.In summary, these data suggest that ethanol exposure may trigger myocardial dysfunction through a mechanism associated with AMPK-mTORC1-ULK1-mediated autophagy.