Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo
Simvastatin induces mitochondrial dysfunction and increased atrogin-1 expression in H9c2 cardiomyocytes and mice in vivo
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DOI：
10.1007/s00204-014-1378-4
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发表时间：
2016-01-01
影响因子：
6.1
通讯作者：
Kraehenbuehl, Stephan
中科院分区：
文献类型：
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作者：
Bonifacio, Annalisa;Mullen, Peter J.;Kraehenbuehl, Stephan
辛伐他汀有效且耐受性良好，不良反应主要影响骨骼肌。骨骼肌毒性的重要机制包括线粒体损伤和atrogin-1表达增加。目的是研究辛伐他汀对H9 c2细胞（啮齿类动物心肌细胞系）和雄性C57 BL/6小鼠心脏的毒性机制。10 μ mol/L辛伐他汀作用24 h后，H9 c2细胞耗氧量降低，线粒体膜电位降低，线粒体电子传递链（ETC）几种酶复合物活性降低。细胞ATP水平降低，与AMPK磷酸化、FoxO 3a去磷酸化和核转位以及atrogin-1 mRNA表达增加有关。辛伐他汀处理的H9 c2细胞凋亡的标志物增加。用5 mg/kg/天辛伐他汀给药小鼠21天，心脏重量下降5%，ETC的几种酶复合物活性受损，心脏组织中atrogin-1和细胞凋亡标志物的mRNA表达增加。辛伐他汀在体外或体内均可引起心肌细胞线粒体损伤，导致AMPK活化、FoxO 3a去磷酸化和核转化，并增加atrogin-1的表达。线粒体损伤和atrogin-1表达增加与细胞凋亡和蛋白分解增加相关，这可能导致心肌萎缩。
Simvastatin is effective and well tolerated, with adverse reactions mainly affecting skeletal muscle. Important mechanisms for skeletal muscle toxicity include mitochondrial impairment and increased expression of atrogin-1. The aim was to study the mechanisms of toxicity of simvastatin on H9c2 cells (a rodent cardiomyocyte cell line) and on the heart of male C57BL/6 mice. After, exposure to 10 mu mol/L simvastatin for 24 h, H9c2 cells showed impaired oxygen consumption, a reduction in the mitochondrial membrane potential and a decreased activity of several enzyme complexes of the mitochondrial electron transport chain (ETC). The cellular ATP level was also decreased, which was associated with phosphorylation of AMPK, dephosphorylation and nuclear translocation of FoxO3a as well as increased mRNA expression of atrogin-1. Markers of apoptosis were increased in simvastatin-treated H9c2 cells. Treatment of mice with 5 mg/kg/day simvastatin for 21 days was associated with a 5 % drop in heart weight as well as impaired activity of several enzyme complexes of the ETC and increased mRNA expression of atrogin-1 and of markers of apoptosis in cardiac tissue. Cardiomyocytes exposed to simvastatin in vitro or in vivo sustain mitochondrial damage, which causes AMPK activation, dephosphorylation and nuclear transformation of FoxO3a as well as increased expression of atrogin-1. Mitochondrial damage and increased atrogin-1 expression are associated with apoptosis and increased protein breakdown, which may cause myocardial atrophy.