ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening.
ARC regulates programmed necrosis and myocardial ischemia/reperfusion injury through the inhibition of mPTP opening.
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ARC通过抑制mPTP开放调节程序性坏死和心肌缺血/再灌注损伤
DOI：
10.1016/j.redox.2018.10.023
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发表时间：
2019-01
期刊：
影响因子：
11.4
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Xu T;Ding W;Ao X;Chu X;Wan Q;Wang Y;Xiao D;Yu W;Li M;Yu F;Wang J
坏死是心肌梗死（MI）、缺血/再灌注（I/R）损伤和心力衰竭等心脏病理过程中心肌损伤的关键因素。越来越多的证据表明，坏死的多个方面是受到编程和严格调控的，因此针对坏死过程已成为心肌保护的新趋势。多种细胞信号传导途径与坏死细胞死亡有关，例如死亡受体介导的外源性和线粒体内源性途径。然而，心肌坏死的确切机制仍不清楚。在这项研究中，我们发现具有半胱天冬酶募集结构域（ARC）的凋亡阻遏蛋白参与线粒体内在途径，并通过阻止线粒体通透性转换孔（mPTP）的开放来抑制心肌坏死。 ARC 减轻了心肌细胞系 H9c2 暴露于 500μM 过氧化氢 (H2O2) 时引发的坏死性细胞死亡。在小鼠中，ARC 可改善 I/R 损伤期间的心肌坏死、减少心肌梗塞面积并改善长期心脏功能。从机制上讲，ARC 对坏死的抑制依赖于其线粒体定位，并且 ARC 通过靶向 mPTP 的主要调节因子 CypD 来阻止 mPTP 的开放。此外，在坏死过程中，ARC表达在转录水平上受到转录因子p53的负向调节。这些发现确定了ARC在心肌坏死中的新作用，并描绘了缺血和氧化应激诱导的心肌损伤期间p53-ARC-CypD/mPTP坏死通路，这可以为心脏保护提供新策略。 ARC 可减轻暴露于 H2O2 的心肌细胞和缺血/再灌注损伤小鼠心脏的坏死。 ARC 对坏死的减弱取决于其线粒体定位及其对 mPTP 打开的抑制。 ARC 针对 CypD 并阻止 mPTP 打开。 p53 通过在转录水平抑制 ARC 表达来调节坏死。
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. ARC attenuates necrosis both in cardiomyocytes exposed to H2O2 and in mouse hearts with ischemia/reperfusion injury. The attenuation of necrosis by ARC depends on its mitochondrial localization and its inhibition of mPTP opening. ARC targets CypD and prevents mPTP opening. p53 regulates necrosis by suppression of ARC expression at the transcriptional level.
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影响因子：
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作者：
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通讯作者：
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