Cardioprotection of Ischemia/Reperfusion Injury by Cholesterol-Dependent MG53-Mediated Membrane Repair
Cardioprotection of Ischemia/Reperfusion Injury by Cholesterol-Dependent MG53-Mediated Membrane Repair
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胆固醇依赖性 MG53 介导的膜修复对缺血/再灌注损伤的心脏保护作用
DOI：
10.1161/circresaha.109.215822
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发表时间：
2010-07-09
影响因子：
20.1
通讯作者：
Cheng, Heping
中科院分区：
文献类型：
--
作者：
Wang, Xianhua;Xie, Wenjun;Cheng, Heping
原理：未修复的心肌细胞膜损伤导致不可替代的细胞损失，导致心肌纤维化并最终导致心力衰竭。然而，心脏膜修复的细胞和分子机制在很大程度上是未知的。MG 53是一种新发现的横纹肌特异性蛋白，参与骨骼肌膜修复。但MG 53在心脏中的作用尚未确定。目的：我们试图研究MG 53是否介导心肌细胞的膜修复，如果是这样，MG 53介导的心肌细胞膜修复的细胞和分子机制。此外，我们确定了MG 53介导的膜修复可能的心脏保护作用。方法和结果：我们证明了MG 53对心肌细胞的紧急膜修复反应至关重要，并保护心脏免受应激诱导的心肌细胞损失。通过机械、电、化学或代谢损伤破坏肌膜，导致MG 53向损伤部位快速且稳健的易位。MG 53的消融防止了完整心脏中红外激光诱导的膜损伤后的肌膜再封闭，并加剧了缺血/再灌注损伤期间的线粒体功能障碍和心肌细胞损失。出乎意料的是，MG 53介导的心脏膜修复是由胆固醇依赖性机制介导的：膜胆固醇的消耗被消除，并且其恢复恢复了损伤诱导的MG 53膜易位。MG 53的氧化还原状态不影响MG 53易位的起始，而MG 53氧化赋予膜修复补丁稳定性。结论：因此，胆固醇依赖性MG 53介导的膜修复是一种重要的、迄今为止尚未被认识到的针对多种损伤的心脏保护机制，并且可能具有重要的治疗意义。
Rationale: Unrepaired cardiomyocyte membrane injury causes irreplaceable cell loss, leading to myocardial fibrosis and eventually heart failure. However, the cellular and molecular mechanisms of cardiac membrane repair are largely unknown. MG53, a newly identified striated muscle-specific protein, is involved in skeletal muscle membrane repair. But the role of MG53 in the heart has not been determined. Objective: We sought to investigate whether MG53 mediates membrane repair in cardiomyocytes and, if so, the cellular and molecular mechanism underlying MG53-mediated membrane repair in cardiomyocytes. Moreover, we determined possible cardioprotective effect of MG53-mediated membrane repair. Methods and Results: We demonstrated that MG53 is crucial to the emergency membrane repair response in cardiomyocytes and protects the heart from stress-induced loss of cardiomyocytes. Disruption of the sarcolemmal membrane by mechanical, electric, chemical, or metabolic insults caused rapid and robust translocation of MG53 toward the injury sites. Ablation of MG53 prevented sarcolemmal resealing after infrared laser–induced membrane damage in intact heart, and exacerbated mitochondrial dysfunction and loss of cardiomyocytes during ischemia/reperfusion injury. Unexpectedly, the MG53-mediated cardiac membrane repair was mediated by a cholesterol-dependent mechanism: depletion of membrane cholesterol abolished, and its recovery restored injury-induced membrane translocation of MG53. The redox status of MG53 did not affect initiation of MG53 translocation, whereas MG53 oxidation conferred stability to the membrane repair patch. Conclusions: Thus, cholesterol-dependent MG53-mediated membrane repair is a vital, heretofore unappreciated cardioprotective mechanism against a multitude of insults and may bear important therapeutic implications.