Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2
Hydrogen peroxide-induced necrotic cell death in cardiomyocytes is independent of matrix metalloproteinase-2
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DOI：
10.1016/j.tiv.2013.04.013
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发表时间：
2013-09-01
影响因子：
3.2
通讯作者：
Schulz, Richard
中科院分区：
文献类型：
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作者：
Ali, Mohammad A. M.;Kandasamy, Arulmozhi D.;Schulz, Richard
基质金属蛋白酶-2(MMP2)可以分解细胞外和细胞内的蛋白质。活性氧在转录和翻译后水平激活了基质金属蛋白酶-2，因此基质金属蛋白酶-2的激活被认为是氧化应激损伤的早期事件。虽然过氧化氢被广泛用于触发氧化应激诱导的细胞死亡，但心肌细胞的细胞死亡类型(凋亡和坏死)仍然存在争议，具体取决于使用的浓度和暴露时间。我们仔细研究了不同浓度(50-500 mU M)的过氧化氢在暴露后不同时间段诱导新生大鼠心肌细胞死亡的方式，以确定基质金属蛋白酶-2是否参与了过氧化氢诱导的心肌细胞死亡。用过氧化氢处理心肌细胞后，心肌细胞的基质金属蛋白酶-2水平/活性升高，最大作用出现在200 mU M处。过氧化氢通过破坏质膜而导致坏死性细胞死亡，表现为乳酸脱氢酶以浓度和时间依赖的方式释放，以及PARP-1的坏死性裂解。Caspase-3的断裂/激活和PARP-1的凋亡断裂均不存在，说明细胞凋亡的作用较弱。选择性基质金属蛋白酶抑制剂的预处理不能预防过氧化氢诱导的坏死。综上所述，过氧化氢可增加心肌细胞中基质金属蛋白酶-2的水平/活性，并诱导坏死性细胞死亡，但后者的作用不依赖于基质金属蛋白酶-2。(C)2013爱思唯尔有限公司。保留所有权利。
Matrix metalloproteinase-2 (MMP-2) is well known to proteolyse both extracellular and intracellular proteins. Reactive oxygen species activate MMP-2 at both transcriptional and post-translational levels, thus MMP-2 activation is considered an early event in oxidative stress injury. Although hydrogen peroxide is widely used to trigger oxidative stress-induced cell death, the type of cell death (apoptosis vs. necrosis) in cardiomyocytes is still controversial depending on the concentration used and the exposure time. We carefully investigated the mode of cell death in neonatal rat cardiomyocytes induced by different concentrations (50-500 mu M) of hydrogen peroxide at various time intervals after exposure and determined whether MMP-2 is implicated in hydrogen peroxide-induced cardiomyocyte death. Treating cardiomyocytes with hydrogen peroxide led to elevated MMP-2 level/activity with maximal effects seen at 200 mu M. Hydrogen peroxide caused necrotic cell death by disrupting the plasmalemma as evidenced by the release of lactate dehydrogenase in a concentration- and time-dependant manner as well as the necrotic cleavage of PARP-1. The absence of both caspase-3 cleavage/activation and apoptotic cleavage of PARP-1 illustrated the weak contribution of apoptosis. Pre-treatment with selective MMP inhibitors did not protect against hydrogen peroxide-induced necrosis. In conclusion hydrogen peroxide increases MMP-2 level/activity in cardiomyocytes and induces necrotic cell death, however, the later effect is MMP-2 independent. (C) 2013 Elsevier Ltd. All rights reserved.