ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening.

Necrosis is a key factor in myocardial injury during cardiac pathological processes, such as myocardial infarction (MI), ischemia/reperfusion (I/R) injury and heart failure. Increasing evidence suggests that several aspects of necrosis are programmed and tightly regulated, so targeting the necrosis process has become a new trend for myocardial protection. Multiple cellular signaling pathways have been implicated in necrotic cell death, such as the death receptor-mediated extrinsic and mitochondrial intrinsic pathways. However, the precise mechanisms underlying myocardial necrosis remain unclear. In this study, we showed that apoptosis repressor with caspase recruitment domain (ARC) participated in the mitochondrial intrinsic pathway and inhibited myocardial necrosis by preventing the opening of the mitochondrial permeability transition pore (mPTP). ARC attenuated necrotic cell death triggered by exposure to 500 μM hydrogen peroxide (H2O2) in the cardiomyocyte cell line H9c2. In mice, ARC ameliorated myocardial necrosis, reduced the myocardial infarct size and improved long-term heart function during I/R injury. Mechanistically, it has been shown that the inhibition of necrosis by ARC was dependent on its mitochondrial localization and that ARC prevented the opening of mPTP by targeting CypD, the main regulator of mPTP. In addition, ARC expression was negatively regulated by the transcription factor p53 at the transcriptional level during the necrosis process. These findings identified the novel role of ARC in myocardial necrosis and delineated the p53-ARC-CypD/mPTP necrosis pathway during ischemia- and oxidative stress-induced myocardial damage, which can provide a new strategy for cardiac protection.