Analysis of the role of mitochondrial transcription factor in cardiovascular diseases and the development of novel therapeutic strategies

最近的实验和临床研究表明，氧化应激在心力衰竭中增强。在衰竭的心脏中，氧自由基的产生增加，而抗氧化酶的活性保持正常。线粒体电子传递是产生氧自由基的酶促来源，也是对抗氧化诱导的衰竭心肌损伤的目标。线粒体中氧自由基产生的慢性增加可导致线粒体DNA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、凋亡和间质纤维化。这些细胞事件在不适应心脏重构和心力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。过氧化物还氧素-3 （Prx-3）、线粒体抗氧化剂或线粒体转录因子A （TFAM）的过表达可以改善衰竭心脏线粒体DNA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阻止了。因此，激活过氧化物还原素-3或TFAM表达可以改善心肌衰竭的病理生理过程。抑制氧化应激和线粒体DNA损伤可能是治疗包括心力衰竭在内的各种心血管疾病的新的和潜在有效的治疗策略。

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 whereas antioxidant enzyme activities are preserved normal. 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 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 mitochondrial DNA damage are good therapeutic targets. Overexpression of peroxiredoxin-3 (Prx-3), mitochondrial antioxidant, or mitochondrial transcription factor A (TFAM) could ameliorate the decline in mitochondrial DNA copy number in failing hearts. Consistent with alterations in mitochondrial DNA, the decrease in oxidative capacities was also prevented. Therefore, the activation of peroxiredoxin-3 or TFAM expression could ameliorate the pathophysiological processes seen in myocardial failure. Inhibition of oxidative stress and mitochondrial DNA damage could be the novel and potentially effective treatment strategies for various cardiovascular diseases including heart failure.