ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity

被引:51
作者
An, Junfeng [2 ,3 ]
Li, Peifeng [2 ,3 ,4 ]
Li, Jincheng [2 ,3 ]
Dietz, Rainer [2 ,3 ]
Donath, Stefan [1 ,2 ,3 ]
机构
[1] HELIOS Klinikum Berlin Buch, D-13125 Berlin, Germany
[2] Humboldt Univ, Dept Cardiol, Expt Clin Res Ctr, Berlin, Germany
[3] HELIOS Clin GmBH, Max Delbruck Ctr Mol Med, Berlin, Germany
[4] Univ Illinois, Coll Med, Chicago, IL 60612 USA
来源
JOURNAL OF MOLECULAR MEDICINE-JMM | 2009年 / 87卷 / 04期
关键词
Apoptosis; Cardiomyopathy; Gene therapy; Heart failure; Myocyte; CASPASE RECRUITMENT DOMAIN; CARDIAC-MUSCLE-CELLS; PROTEIN ARC; APOPTOSIS REPRESSOR; IN-VIVO; BAX; DEATH; DEGRADATION; ACTIVATION; INHIBITOR;
D O I
10.1007/s00109-008-0434-z
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Despite its complexity of action, doxorubicin (Dox)-induced cardiomyopathy eventually results in loss of cardiac myocytes which further contributes to the development of overt heart failure. In the present study, we examined the relevance of the apoptosis repressor with caspase recruitment domain (ARC) on cardiac myocyte survival and its underlying mechanisms in a model of Dox-induced cardiotoxicity. Exposure of neonatal rat ventricular cardiomyocytes with Dox resulted in a downregulation of ARC mRNA and protein levels that occurred in a pre-translational and post-translational manner and led to a significant induction of apoptosis. Proteasomal inhibitors partially rescued both Dox-induced downregulation of ARC protein and induction of apoptosis. Knockdown of endogenous ARC sensitised cardiomyocytes to undergo apoptosis upon treatment with Dox. In contrast, enforced expression of ARC by adenoviral-mediated gene transfer dramatically increased the resistance of cardiomyocytes to undergo apoptotic cell death following Dox administration. In response to Dox, Bax translocated from cytosol to mitochondria where it resulted in dissipation of the mitochondrial membrane potential, cytochrome c release and activation of caspases -3 and -9. ARC prevented Bax translocation to the mitochondrium and thereby blocked the activation of the mitochondrial apoptotic death pathway in a t-Bid and caspase-8-independent manner. In this study, we provide evidence for the protective role of anti-apoptotic ARC in Dox-induced cardiotoxicity, which makes this molecule an interesting target for future therapies.
引用
收藏
页码:401 / 410
页数:10
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