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

线粒体转录因子在心血管疾病中的作用分析及新治疗策略的开发

基本信息

批准号：
17390223
负责人：
TSUTSUI Hiroyuki
金额：
$ 10.5万
依托单位：
Hokkaido University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

项目摘要

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.

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，而抗氧化酶活性保持正常。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损伤的灾难性循环，以及功能下降，进一步的氧自由基产生，以及细胞损伤。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，氧化能力的下降也得到了防止。因此，激活过氧化还蛋白-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损伤可能成为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。

项目成果

期刊论文数量（0）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Contribution of polymorphisms in UDP-glucuronosyltransferase and CYP2D6 to the individual variation in disposition of carvedilol.

DOI：
发表时间：
2006
期刊：
Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques
影响因子：
0
作者：
Y. Takekuma;T. Takenaka;M. Kiyokawa;Koujiro Yamazaki;H. Okamoto;A. Kitabatake;H. Tsutsui;M. Sugawara
通讯作者：
Y. Takekuma;T. Takenaka;M. Kiyokawa;Koujiro Yamazaki;H. Okamoto;A. Kitabatake;H. Tsutsui;M. Sugawara

Elevated serum C-reactive protein levels as a predictive indicator for subsequent renal impairment in patients with acute heart failure.

血清 C 反应蛋白水平升高可作为急性心力衰竭患者后续肾功能损害的预测指标。