Oxidative stress causes heart failure with impaired mitochondrial respiration
Oxidative stress causes heart failure with impaired mitochondrial respiration
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DOI：
10.1074/jbc.m602118200
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发表时间：
2006-11-03
影响因子：
4.8
通讯作者：
Shirasawa, Takuji
中科院分区：
文献类型：
--
作者：
Nojiri, Hidetoshi;Shimizu, Takahiko;Shirasawa, Takuji
老年人以年龄依赖性方式不知不觉地表现出心力衰竭的症状，例如呼吸困难和/或身体残疾。虽然以前的研究表明，氧化应激在心力衰竭的发展中起着病理作用，但迄今为止还没有直接的证据。为了研究心脏氧化应激的病理意义，我们产生了心脏/肌肉特异性锰超氧化物歧化酶缺陷小鼠。突变小鼠发展为进行性充血性心力衰竭，线粒体呼吸存在特定分子缺陷。在本文中，我们首次表明，氧化应激引起线粒体的特定形态学变化，过量形成的超氧化物（O-2（中心点）），ATP的减少，和基因的转录改变与心力衰竭方面的心脏收缩力。因此，施用超氧化物歧化酶模拟物显著改善了症状。提示线粒体内产生的O-2（中心点）在心力衰竭的发生、发展中起着重要作用。我们在这里提出了一个真正的模型，人类心力衰竭与氧化应激治疗干预的价值。
Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O-2(center dot)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O-2(center dot) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.