MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning
MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning
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DOI：
10.1161/circulationaha.110.954628
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发表时间：
2010-06-15
期刊：
影响因子：
37.8
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
--
作者：
Cao, Chun-Mei;Zhang, Yan;Xiao, Rui-Ping
背景-缺血性心脏病是西方国家最大的死亡原因。缺血预处理（IPC）可减轻心肌缺血的有害作用，其中短暂缺血可保护随后的严重缺血/再灌注损伤。IPC激活多种信号传导途径，包括再灌注损伤补救激酶途径（主要是PI 3 K-Akt-糖原合成酶激酶-3 β [GSK 3 β]和ERK 1/2）和涉及JAK-STAT 3轴激活的存活激活因子增强途径。然而，IPC的基本机制是知之甚少。方法和结果-在本研究中，我们定义MG 53，肌肉特异性TRIM家族蛋白，作为心脏IPC机械的重要组成部分。分别对灌流小鼠心脏或新生大鼠心肌细胞施加缺血/再灌注或缺氧/氧化应激，导致MG 53下调，IPC可以防止缺血/再灌注诱导的MG 53表达下降。MG 53缺乏会增加心肌对缺血/再灌注损伤的脆弱性并取消IPC保护。MG 53的过表达减弱了缺氧和H2 O2诱导的心肌细胞死亡，而MG 53的敲低增强了缺氧和H2 O2诱导的心肌细胞死亡。MG 53的心脏保护作用可归因于MG 53依赖性的小窝蛋白-3与磷脂酰肌醇3激酶的相互作用以及随后的再灌注损伤补救激酶途径的激活，而不改变幸存者激活因子增强途径。从而鉴定了用于治疗缺血性心脏病的潜在重要的新治疗靶点。（循环。2010; 121：2565-2574）。
Background-Ischemic heart disease is the greatest cause of death in Western countries. The deleterious effects of cardiac ischemia are ameliorated by ischemic preconditioning (IPC), in which transient ischemia protects against subsequent severe ischemia/reperfusion injury. IPC activates multiple signaling pathways, including the reperfusion injury salvage kinase pathway (mainly PI3K-Akt-glycogen synthase kinase-3 beta [GSK3 beta] and ERK1/2) and the survivor activating factor enhancement pathway involving activation of the JAK-STAT3 axis. Nevertheless, the fundamental mechanism underlying IPC is poorly understood.Methods and Results-In the present study, we define MG53, a muscle-specific TRIM-family protein, as a crucial component of cardiac IPC machinery. Ischemia/reperfusion or hypoxia/oxidative stress applied to perfused mouse hearts or neonatal rat cardiomyocytes, respectively, causes downregulation of MG53, and IPC can prevent ischemia/reperfusion-induced decrease in MG53 expression. MG53 deficiency increases myocardial vulnerability to ischemia/reperfusion injury and abolishes IPC protection. Overexpression of MG53 attenuates whereas knockdown of MG53 enhances hypoxia-and H2O2-induced cardiomyocyte death. The cardiac protective effects of MG53 are attributable to MG53-dependent interaction of caveolin-3 with phosphatidylinositol 3 kinase and subsequent activation of the reperfusion injury salvage kinase pathway without altering the survivor activating factor enhancement pathway.Conclusions-These results establish MG53 as a primary component of the cardiac IPC response, thus identifying a potentially important novel therapeutic target for the treatment of ischemic heart disease. (Circulation. 2010; 121: 2565-2574.)