Cardioprotection of ischemia/reperfusion injury by cholesterol-dependent MG53-mediated membrane repair.
BACKGROUND
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.


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.
Wang
Xianhua
X
Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China. xianhua@pku.edu.cn
Xie
Wenjun
W
Zhang
Yi
Y
Lin
Peihui
P
Han
Liang
L
Han
Peidong
P
Wang
Yanru
Y
Chen
Zheng
Z
Ji
Guangju
G
Zheng
Ming
M
Weisleder
Noah
N
Xiao
Rui-Ping
RP
Takeshima
Hiroshi
H
Ma
Jianjie
J
Cheng
Heping
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002784:Cholesterol / Q000502:physiology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology
D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D002784:Cholesterol