Targeting mitochondria for resuscitation from cardiac arrest.
Targeting mitochondria for resuscitation from cardiac arrest.
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DOI：
10.1097/ccm.0b013e31818a89f4
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发表时间：
2008-11
影响因子：
8.8
通讯作者：
Gazmuri RJ
中科院分区：
文献类型：
--
作者：
Ayoub IM;Radhakrishnan J;Gazmuri RJ
心脏骤停的恢复需要通过用含氧血再灌注缺血可变时间段的组织来重建有氧代谢。然而，再灌注同时激活了无数的致病机制，导致所谓的“再灌注损伤”。再灌注损伤的中心是线粒体，其作为损伤的效应器和靶起着关键作用。室颤动物模型的研究表明，限制心肌细胞溶质Na+过载可减弱线粒体Ca 2+过载并维持氧化磷酸化，氧化磷酸化是线粒体的主要生物能量功能。这种效应与功能性心肌益处相关，例如胸外按压期间心肌顺应性的保持和自主循环恢复后心肌功能障碍的减弱。在类似的室颤动物模型中进行的其他研究表明，线粒体损伤导致线粒体凋亡途径的激活;其特征在于细胞色素c释放到胞质溶胶中，半胱天冬酶-9水平降低，半胱天冬酶-3的激活与左心室功能的显著降低一致。细胞色素c也会“泄漏”到血液中，达到与存活率成反比的水平。这些数据表明，线粒体通过调节能量代谢和信号转导凋亡级联反应在心脏复苏过程中发挥关键作用，靶向线粒体可能代表心脏复苏的一种有前途的策略。
Reversal of cardiac arrest requires reestablishment of aerobic metabolism by reperfusion with oxygenated blood of tissues that have been ischemic for variables periods of time. However, re-perfusion concomitantly activates a myriad of pathogenic mechanisms causing what is known as “reperfusion injury.” At the center of reperfusion injury are mitochondria, playing a critical role as effectors and targets of injury. Studies in animal models of ventricular fibrillation have shown that limiting myocardial cytosolic Na+ overload attenuates mitochondrial Ca2+ overload and maintains oxidative phosphorylation, which is the main bioenergetic function of mitochondria. This effect is associated with functional myocardial benefits such as preservation of myocardial compliance during chest compression and attenuation of myocardial dysfunction after return of spontaneous circulation. Additional studies in similar animal models of ventricular fibrillation have shown that mitochondrial injury leads to activation of the mitochondrial apoptotic pathway; characterized by the release of cytochrome c to the cytosol, reduction of caspase-9 levels, and activation of caspase-3 coincident with marked reduction in left ventricular function. Cytochrome c also “leaks” into the bloodstream attaining levels which are inversely proportional to survival. These data indicate that mitochondria play a key role during cardiac resuscitation by modulating energy metabolism and signaling apoptotic cascades and that targeting mitochondria could represent a promising strategy for cardiac resuscitation.
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