MG53 Constitutes a Primary Determinant of Cardiac Ischemic Preconditioning

Abstract

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␤ [GSK3␤] 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 H 2 O 2 -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.)Key Words: hypoxia Ⅲ ischemia Ⅲ myocardial infarction Ⅲ myocytes Ⅲ stress I schemic heart disease remains the greatest cause of mortality in Western countries and the predicted leading source of mortality worldwide by 2020. 1 Blockage of heart blood flow leads to myocardial ischemia. Persistent ischemia causes myocardial infarctions, resulting in profound myocyte death, irreversible myocardial damage, and a permanent loss of contractile mass. Timely reperfusion of ischemic heart is the only way to preserve cardiac cell viability. However, reperfusion can trigger further damage to the myocardium (ie, ischemia/reperfusion [IR] injury) via reactive oxygen species-induced oxidative stress, calcium overload, or calpain activation. [2][3][4] Both ischemic injury and subsequent IR injury after restoration of blood flow represent important therapeutic targets. Editorial on p 2547 Clinical Perspective on p 2574Interventional approaches against IR injury have centered on the study of ischemic preconditioning (IPC), in which nonlethal ischemic stress to the heart (IPC) protects against subsequent lethal IR injury in the heart. 5-7 IPC is the most powerful intrinsic cellular mechanism to protect the heart as well as other organs, such as brain, liver, and kidney, from IR injury. 8 -11 A variety of signaling mo...

Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart

“…7C) were predominantly distributed in heavy fractions in perfusion hearts, and their phosphorylation level was significantly increased in IPC hearts. In addition, IPC also greatly increased caveolae-associated p-AKT, but not p-GSK-3␤, which was consistent with other findings, i.e., caveolaeenriched p-ERK1/2 and p-AKT upon stress exposure (5,53). Interestingly, IPC-induced changes and redistribution of these cellular signals were blocked by NPS2143 treatment, suggesting activation of CaSR is necessary for activating cardioprotective signaling.…”

Podocalyxin promotes cisplatin chemoresistance in osteosarcoma cells through phosphatidylinositide 3-kinase signaling

“…PI3K activity was determined using the PI3K Activity ELISA kit, according to the manufacturer's instructions (20,21). For BKM120 treatment, cells were treated with BKM120 (50 µM) for 48 h. For direct functional assessment of PI3K activity, PI3K was isolated by immunoprecipitation using an anti-PI3K antibody (cat.…”

MicroRNA-21 regulation of the progression of viral myocarditis to dilated cardiomyopathy

“…They are subject to tight control at multiple levels, including differential localization, post-translational modification and the regulation of protein levels. SPRY participates in multiple physiological and pathological processes, including acute membrane repair, myogenesis in skeletal muscle and cardiac ischemic preconditioning (12,(15)(16)(17). Thum et al identified that SPRY1 was a direct target of miRNA-21 and mediated the effect of miRNA-21 in cardiac fibroblasts (18).…”