ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity

Item Type:	Article
Title:	ARC is a critical cardiomyocyte survival switch in doxorubicin cardiotoxicity
Creators Name:	An, J. and Li, P. and Li, J. and Dietz, R. and Donath, S.
Abstract:	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.
Keywords:	Apoptosis, Cardiomyopathy, Gene Therapy, Heart Failure, Myocyte, Animals, Rats
Source:	Journal of Molecular Medicine
ISSN:	0946-2716
Publisher:	Springer
Volume:	87
Number:	4
Page Range:	401-410
Date:	April 2009
Official Publication:	https://doi.org/10.1007/s00109-008-0434-z
PubMed:	View item in PubMed

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