Role of oxidative mitochondrial DNA damage and its preventive mechanisms in the development and progression of heart failure

以往的基础科学、临床科学和人口科学都推动了心衰的现代治疗。然而，它的功效仍然有限。解决这一关键问题的一个重要途径是基于对心肌重构和衰竭病理生理学的新见解，开发新的治疗策略。我们的方法是通过调节线粒体氧化应激来开发治疗策略。在衰竭的心脏中，氧自由基是由线粒体电子传递缺陷产生的。它们会导致线粒体DNA损伤和功能下降，导致氧自由基的进一步产生。氧化应激通过激活基质金属蛋白酶导致心肌细胞肥大、细胞凋亡和间质纤维化，所有这些都导致心肌重构和衰竭。因此，线粒体氧化应激和DNA损伤是很好的治疗靶点。氧化应激不仅与心衰有关，还与动脉粥样硬化、高血压等多种心血管疾病有关。因此，调节这种适应不良反应的治疗策略绝对应该成为未来广泛研究的目标，而旨在干扰氧化应激的治疗方法，特别是在线粒体内，可能会有更广泛的应用。

Previous basic, clinical, population sciences have advanced the modern treatment of HF. However, its efficacy is still limited. An important approach to solve this crucial issue is the development of novel therapeutic strategies based on a novel insight into the pathophysiology of myocardial remodeling and failure. Our approach is to develop the therapeutic strategy by regulating mitochondrial oxidative stress. In the failing hearts, oxygen radicals are produced by the defects of mitochondrial electron transport. They cause mitochondrial DNA damage and functional decline, leading to the further production of oxygen radicals. Oxidative stress causes myocyte hypertrophy, apoptosis, and interstitial fibrosis by activating matrix metalloproteinases, all of which result in myocardial remodeling and failure. Therefore, mitochondrial oxidative stress and DNA damage are good therapeutic targets. Oxidative stress is involved not only in HF, but also in various cardiovascular diseases including atherosclerosis and hypertension. Therefore, therapeutic strategies to modulate this maladaptive response should definitely become a target for future extensive investigation and therapies designed to interfere with oxidative stress, especially within the mitochondria, could have a broader application.