Oxidative stress, mitochondrial permeability transition pore opening and cell death during hypoxia-reoxygenation in adult cardiomyocytes
Oxidative stress, mitochondrial permeability transition pore opening and cell death during hypoxia-reoxygenation in adult cardiomyocytes
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DOI：
10.1016/j.ejphar.2011.11.036
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发表时间：
2012-01-30
影响因子：
5
通讯作者：
Morin, Didier
中科院分区：
文献类型：
--
作者：
Assaly, Rana;d'Anglemont de Tassigny, Alexandra;Morin, Didier
缺氧/复氧后，活性氧的产生是诱导细胞死亡所必需的，但缺氧期间产生的活性氧对线粒体通透性转换孔（mPTP）开放和细胞死亡的影响尚未确定。在这里，我们设计了一个模型的缺氧/复氧在分离的心肌细胞测量同时活性氧产生，mPTP开放和细胞死亡，以便（i）建立它们之间的因果关系，（ii）调查各种活性氧在mPTP开放的作用。随着缺氧时间的延长，心肌细胞在复氧过程中表现出mPTP开放的百分比增加。抗氧化剂在缺氧时增加了mPTP开放的时间，但在复氧时没有。这与缺氧和复氧的最初几分钟内羟自由基和过氧化氢的下降有关。mPTP开放时间的增加伴随着细胞活力的改善，反映在复氧时超氧化物产生的维持。环孢菌素A延迟了mPTP开放和细胞死亡的时间，尽管在缺氧期间维持活性氧的产生。这些研究结果表明，活性氧的产生先于mPTP开放，缺氧过程中产生的活性氧，特别是羟基自由基和过氧化氢，是诱导mPTP开放所必需的，这取决于缺氧持续时间。(C)2011 Elsevier B. V.保留所有权利。
Reactive oxygen species production is necessary to induce cell death following hypoxia/reoxygenation but the effect of reactive oxygen species produced during hypoxia on mitochondrial permeability transition pore (mPTP) opening and cell death is not established. Here we designed a model of hypoxia/reoxygenation in isolated cardiomyocytes measuring simultaneously reactive oxygen species production, mPTP opening and cell death in order (i) to establish a causal relationship between them, and (ii) to investigate the roles of various reactive oxygen species in mPTP opening. The percentage of cardiomyocytes exhibiting mPTP opening during reoxygenation increased with the duration of hypoxia. Antioxidants increased the time to mPTP opening when present during hypoxia but not at reoxygenation. This was associated with a drop in hydroxyl radical and hydrogen peroxide during hypoxia and the first minutes of reoxygenation. The increase in time to mPTP opening was accompanied by an improvement in cell viability reflected by maintenance of superoxide production at reoxygenation. Cyclosporin A delayed both the time to mPTP opening and cell death despite maintenance of reactive oxygen species production during hypoxia. These findings demonstrate that reactive oxygen species production precedes mPTP opening and that reactive oxygen species produced during hypoxia, particularly hydroxyl radicals and hydrogen peroxide, are necessary to induce mPTP opening which depends on hypoxia duration. (C) 2011 Elsevier B.V. All rights reserved.