Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy
Time-dependent and tissue-specific accumulation of mtDNA and respiratory chain defects in chronic doxorubicin cardiomyopathy
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DOI：
10.1161/01.cir.0000093196.59829.df
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发表时间：
2003-11-11
期刊：
影响因子：
37.8
通讯作者：
Walker, UA
中科院分区：
文献类型：
--
作者：
Lebrecht, D;Setzer, B;Walker, UA
背景：阿霉素引起慢性心肌病，其发病机制尚不清楚。我们调查是否获得性缺陷线粒体DNA（mtDNA）和相互关联的呼吸链功能障碍可能代表一种分子机制，其late onset.Methods and Results-Rats每周静脉注射阿霉素（1 mg/kg）7周，从11周龄开始（组B）。对照组接受生理盐水。C组与B组相同，接受阿霉素治疗，但疗程从41周龄开始。在第48周处死所有大鼠。还在安乐死前6天（D组）或2小时（E组）注射一次阿霉素。检查心脏和骨骼肌。仅B组大鼠出现明显的临床、肉眼、组织学和超微结构心肌病。B组心脏的细胞色素c氧化酶（考克斯）活性最低（为对照组的24%; P=0.003），柠檬酸合酶活性最高（为对照组的135%; P=0.005），超氧化物生成量最高。B组线粒体编码的呼吸亚基COXI表达降低（P
Background-Doxorubicin causes a chronic cardiomyopathy of unknown pathogenesis. We investigated whether acquired defects in mitochondrial DNA (mtDNA) and interconnected respiratory chain dysfunction may represent a molecular mechanism for its late onset.Methods and Results-Rats were treated weekly with intravenous doxorubicin (1 mg/kg) for 7 weeks, starting at 11 weeks of age (group B). Controls received saline. Group C received doxorubicin identically to group B, but the course was started at 41 weeks of age. All rats were killed at week 48. Doxorubicin was also injected once, either 6 days ( group D) or 2 hours (group E) before euthanasia. Heart and skeletal muscle were examined. Only group B rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Group B hearts had the lowest cytochrome c oxidase (COX) activity (24% of controls; P=0.003), the highest citrate synthase activity (135% of controls; P=0.005), and the highest production of superoxide. In group B, the respiratory subunit COXI, which is encoded by mtDNA, was reduced (P