Oxidative stress and mitochondrial DNA damage in heart failure.
Oxidative stress and mitochondrial DNA damage in heart failure.
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DOI：
10.1253/circj.cj-08-0014
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发表时间：
2008-01-01
期刊：
影响因子：
--
通讯作者：
Matsushima, Shouji
中科院分区：
文献类型：
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作者：
Tsutsui, Hiroyuki;Kinugawa, Shintaro;Matsushima, Shouji
最近的实验和临床研究表明，心力衰竭时氧化应激增强。在衰竭的心脏中，氧自由基的产生增加，而抗氧化酶活性则保持不变。线粒体电子传递是氧自由基产生的酶来源，也是对抗氧化剂诱导的衰竭心肌损伤的靶点。线粒体中氧自由基产生的慢性增加可导致线粒体DNA(MtDNA)损伤的灾难性循环，以及功能下降、进一步的氧自由基产生和细胞损伤。活性氧通过激活基质金属蛋白酶诱导心肌细胞肥大、细胞凋亡和间质纤维化。这些细胞事件在心脏适应性不良重塑和衰竭的发生和发展中起着重要作用。因此，氧化应激和线粒体DNA损伤是很好的治疗靶点。过氧化还蛋白-3(PRX-3)、线粒体抗氧化剂或线粒体转录因子A(TFAM)的过表达可改善衰竭心脏mtDNA拷贝数的下降。与线粒体DNA的改变一致，氧化能力的下降也被防止。因此，激活PRX-3或TFAM的表达可以改善心力衰竭的病理生理过程。抑制氧化应激和线粒体DNA损伤可能是治疗心力衰竭的新的和潜在有效的策略。
Recent experimental and clinical studies have suggested that oxidative stress is enhanced in heart failure. The production of oxygen radicals is increased in the failing heart while antioxidant enzyme activities are preserved. Mitochondrial electron transport is an enzymatic source of oxygen radical generation and also a target against oxidant-induced damage in the failing myocardium. Chronic increases in oxygen radical production in the mitochondria can lead to a catastrophic cycle of mitochondrial DNA (mtDNA) damage, as well as functional decline, further oxygen radical generation, and cellular injury. Reactive oxygen species induce myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases. These cellular events play an important role in the development and progression of maladaptive cardiac remodeling and failure. Therefore, oxidative stress and mtDNA damage are good therapeutic targets. Overexpression of peroxiredoxin-3 (Prx-3), mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM) could ameliorate the decline in mtDNA copy number in failing hearts. Consistent with alterations in mtDNA, the decrease in oxidative capacities is also prevented. Therefore, the activation of Prx-3 or TFAM expression could ameliorate the pathophysiological processes seen in myocardial failure. Inhibition of oxidative stress and mtDNA damage could be novel and potentially effective treatment strategies for heart failure.