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

线粒体DNA氧化损伤及其在心力衰竭发生发展中的预防机制

基本信息

批准号：
14370230
负责人：
TSUTSUI Hiroyuki
金额：
$ 8.9万
依托单位：
HOKKAIDO UNIVERSITY (2004)Kyushu University (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370230/
关键词：
Heart failure Mitochondria DNA Electron transport complex ROS Cytokine Myocyte Oxidative stress ミトコンドア

项目摘要

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.

先前的基础、临床、人口科学已经推进了心力衰竭的现代治疗。然而，其功效仍然有限。解决这一关键问题的一个重要方法是基于对心肌重塑和衰竭的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制定治疗策略。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，所有这些都会导致心肌重塑和衰竭。因此，线粒体氧化应激和DNA损伤是很好的治疗靶点。氧化应激不仅与心力衰竭有关，还与动脉粥样硬化和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（尤其是线粒体内氧化应激）的疗法可能会有更广泛的应用。

项目成果

期刊论文数量（86）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oxidative stress mediates tumor necrosis factor-α-induced mitochondrial DNA damage and dysfunction in cardiac myocytes

DOI：
10.1161/01.cir.0000055318.09997.1f
发表时间：
2003-03-18
期刊：
CIRCULATION
影响因子：
37.8
作者：
Suematsu, N;Tsutsui, H;Takeshita, A
通讯作者：
Takeshita, A

Allopurinol improves cardiac dysfunction after ischemia-reperfusion via reduction of oxidative stress in isolated perfused rat hearts

DOI：
发表时间：
2003
期刊：
影响因子：
0
作者：
衣笠良治
通讯作者：
衣笠良治

Targeted deletion of matrix metalloproteinase-2 attenuates early left ventricular rupture and late remodeling after experimental myocardial infarction

基质金属蛋白酶-2的靶向缺失可减轻实验性心肌梗死后的早期左心室破裂和晚期重构

DOI：
发表时间：
2003
期刊：
Am J Physiol Heart Circ Physiol. 285
影响因子：
0
作者：
Hayashidani S;Tsutsui H;Ikeuchi M;Shiomi T;Matsusaka H;Kubota T;Imanaka-Yoshida K;Itoh T;Takeshita A
通讯作者：
Takeshita A

Probucol attenuates left ventricular dysfunction and remodeling in tachycardia-induced heart failure - Roles of oxidative stress and inflammation