Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress

Tools

Item Type:	Article
Title:	Apoptosis repressor with caspase recruitment domain is required for cardioprotection in response to biomechanical and ischemic stress
Creators Name:	Donath, S., Li, P., Willenbockel, C., Al-Saadi, N., Gross, V., Willnow, T.E., Bader, M., Martin, U., Bauersachs, J., Wollert, K.C., Dietz, R. and von Harsdorf, R.
Abstract:	Background - Ischemic heart disease and heart failure are associated with an increased loss of cardiomyocytes due to apoptosis. Whether cardiomyocyte apoptosis plays a causal role in the pathogenesis of heart failure remains enigmatic. The apoptosis repressor with caspase recruitment domain (ARC) is a recently discovered antiapoptotic factor with a highly specific expression pattern in striated muscle and neurons. ARC is a master regulator of cardiac death signaling because it is the only known factor that specifically inhibits both the intrinsic and extrinsic apoptotic death pathway. In this study we attempted to elucidate the physiological role of ARC and to understand pathophysiological consequences resulting from its deletion. Methods and Results - We generated ARC-deficient mice, which developed normally to adulthood and had no abnormality in cardiac morphology and function under resting conditions. On biomechanical stress induced by aortic banding, ARC-deficient mice developed accelerated cardiomyopathy compared with littermate controls, which was characterized by reduced contractile function, cardiac enlargement, and myocardial fibrosis. Likewise, ischemia/reperfusion injury of ARC-deficient mice resulted in markedly increased myocardial infarct sizes. Although in both instances a significant increase in apoptotic cardiomyocytes could be observed in ARC-deficient mice, neither in vitro nor in vivo studies revealed any effect of ARC on classic hypertrophic cardiomyocyte growth responses. The pathophysiological relevance of downregulated ARC levels was underscored by specimens from failing human hearts showing markedly reduced ARC protein levels. Conclusions - Our study identifies a tissue-specific antiapoptotic factor that is downregulated in human failing myocardium and that is required for cardioprotection in pressure overload and ischemia.
Keywords:	Apoptosis, Apoptosis Regulatory Proteins, Biomechanics, Blood Pressure, Down-Regulation, Fibrosis, Heart Failure, Knockout Mice, Muscle Proteins, Myocardial Infarction, Myocardial Ischemia, Physiological Stress, Animals, Mice
Source:	Circulation
ISSN:	0009-7322
Publisher:	American Heart Association
Volume:	113
Number:	9
Page Range:	1203-1212
Date:	7 March 2006
Official Publication:	https://doi.org/10.1161/CIRCULATIONAHA.105.576785
PubMed:	View item in PubMed

Repository Staff Only: item control page