Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure.
Mitochondrial oxidative stress mediates angiotensin II-induced cardiac hypertrophy and Galphaq overexpression-induced heart failure.
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DOI：
10.1161/circresaha.110.232306
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发表时间：
2011-04-01
影响因子：
20.1
通讯作者：
Rabinovitch PS
中科院分区：
文献类型：
--
作者：
Dai DF;Johnson SC;Villarin JJ;Chin MT;Nieves-Cintrón M;Chen T;Marcinek DJ;Dorn GW 2nd;Kang YJ;Prolla TA;Santana LF;Rabinovitch PS
线粒体功能障碍与多种心血管疾病有关;然而，线粒体氧化应激和DNA损伤在高血压性心肌病中的作用尚不清楚。我们通过使用过表达针对线粒体和过氧化物酶体的过氧化氢酶的遗传小鼠模型来评估线粒体活性氧（ROS）对心脏肥大和衰竭的贡献。血管紧张素II增加心肌细胞中的线粒体ROS，伴随着血管紧张素II处理的小鼠心脏中线粒体蛋白羰基增加、线粒体DNA缺失、自噬增加和线粒体生物发生的信号传导。线粒体ROS在血管紧张素II诱导的心肌病中的因果作用通过以下观察结果显示：过表达靶向线粒体的过氧化氢酶的小鼠，而不是过表达野生型过氧化物酶体过氧化氢酶的小鼠，对血管紧张素II诱导的心脏肥大、纤维化和线粒体损伤以及Gαq过表达诱导的心力衰竭具有抗性。此外，由齐多夫定给药或线粒体聚合酶γ的纯合突变诱导的线粒体DNA的原发性损伤也显示直接有助于心脏肥大、纤维化和衰竭的发展。这些数据表明线粒体ROS在心肌肥厚和心力衰竭中的关键作用，并支持潜在的使用心肌靶向抗氧化剂预防和治疗高血压性心肌病。
Mitochondrial dysfunction has been implicated in several cardiovascular diseases; however, the roles of mitochondrial oxidative stress and DNA damage in hypertensive cardiomyopathy are not well understood. We evaluated the contribution of mitochondrial reactive oxygen species (ROS) to cardiac hypertrophy and failure by using genetic mouse models overexpressing catalase targeted to mitochondria and to peroxisomes. Angiotensin II increases mitochondrial ROS in cardiomyocytes, concomitant with increased mitochondrial protein carbonyls, mitochondrial DNA deletions, increased autophagy and signaling for mitochondrial biogenesis in hearts of Angiotensin II treated mice. The causal role of mitochondrial ROS in Angiotensin II-induced cardiomyopathy is shown by the observation that mice that overexpress catalase targeted to mitochondria, but not mice that overexpress wild-type peroxisomal catalase, are resistant to cardiac hypertrophy, fibrosis and mitochondrial damage induced by Angiotensin II, as well as heart failure induced by overexpression of Gαq. Furthermore, primary damage to mitochondrial DNA, induced by zidovudine administration or homozygous mutation of mitochondrial polymerase gamma, is also shown to contribute directly to the development of cardiac hypertrophy, fibrosis and failure. These data indicate the critical role of mitochondrial ROS in cardiac hypertrophy and failure and support the potential use of mitochondrial-targeted antioxidants for prevention and treatment of hypertensive cardiomyopathy.