Zhang Y, Lin PH, Han L, Han PD, Wang YR, Chen Z, Ji GJ, Zheng M, Weisleder N, Xiao RP, Takeshima H, Ma JJ, Cheng HP. Cardioprotection of Ischemia/Reperfusion Injury by Cholesterol-Dependent MG53-Mediated Membrane Repair. Circulation Research. 2010, 1
Rationale: Unrepaired cardiomyocyte membrane injury causes irreplaceable cell loss, leading to myocardial fibrosisand eventually heart failure. However, the cellular and molecular mechanisms of cardiac membrane repair arelargely 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, thecellular 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 incardiomyocytes and protects the heart from stress-induced loss of cardiomyocytes. Disruption of the sarcolemmalmembrane by mechanical, electric, chemical, or metabolic insults caused rapid and robust translocation of MG53toward the injury sites. Ablation of MG53 prevented sarcolemmal resealing after infrared laser–inducedmembrane damage in intact heart, and exacerbated mitochondrial dysfunction and loss of cardiomyocytes duringischemia/reperfusion injury. Unexpectedly, the MG53-mediated cardiac membrane repair was mediated by acholesterol-dependent mechanism: depletion of membrane cholesterol abolished, and its recovery restoredinjury-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.
