title: Cardioprotection of ischemia/reperfusion injury by cholesterol-dependent MG53-mediated membrane repair.
abstract: 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.
authors.affiliation: Institute of Molecular Medicine, State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, China. xianhua@pku.edu.cn
authors.forename: Xianhua
authors.initials: X
authors.lastname: Wang
authors.forename: Wenjun
authors.initials: W
authors.lastname: Xie
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Peihui
authors.initials: P
authors.lastname: Lin
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Peidong
authors.initials: P
authors.lastname: Han
authors.forename: Yanru
authors.initials: Y
authors.lastname: Wang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Chen
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.forename: Ming
authors.initials: M
authors.lastname: Zheng
authors.forename: Noah
authors.initials: N
authors.lastname: Weisleder
authors.forename: Rui-Ping
authors.initials: RP
authors.lastname: Xiao
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takeshima
authors.forename: Jianjie
authors.initials: J
authors.lastname: Ma
authors.forename: Heping
authors.initials: H
authors.lastname: Cheng
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; C538824:MG53 protein, mouse; D008565:Membrane Proteins; D002784:Cholesterol