Apoptosis Repressor With Caspase Recruitment Domain Is Required for Cardioprotection in Response to Biomechanical and Ischemic Stress

Abstract

on behalf of the German Heart Failure Network 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.

The Apoptosis Inhibitor ARC Undergoes Ubiquitin-Proteasomal-mediated Degradation in Response to Death Stimuli

“…These data suggest that changes in ARC transcription and mRNA stability do not play major roles in regulating ARC protein levels in this context. These results are consistent with measurements in failing human hearts (18). In contrast, pulse-chase experiments in several cell types demonstrated marked decreases in ARC protein stability in response to different apoptotic stimuli.…”

“…Conversely, knock down of endogenous ARC promotes activation of both pathways (12). Similarly, inactivation of ARC in the mouse increases cardiac myocyte apoptosis in models of myocardial ischemia-reperfusion and hemodynamic overload (18). These * This work was supported by National Institutes of Health Grants R01HL60665, R01HL61550, R01HL80607 (to R. N. K.), and P60DK020541 (to Y-J.…”

Inhibition of Endoplasmic Reticulum Stress–Induced Apoptosis of Melanoma Cells by the ARC Protein

“…This suggests that removal of the inhibitory effect of ARC may be required to ensure optimal induction of apoptosis by ER stress (14,24,27,28). In support of this, degradation of ARC by the ubiquitin-proteasome pathway has been reported to be an initiating event in apoptosis induced by varying stimuli (27,28).…”

Doxorubicin-induced chronic dilated cardiomyopathy—the apoptosis hypothesis revisited

“…Hence, increased protection against MOMP after DOX exposure, and hence a counter-priming, is indicated by elevation of the anti-apoptotic protein BCL2 [23], by an increase of BCL2/BAX protein ratio [57] and elevation of the anti-apoptotic gene ARC in rat hearts [58,59]. As most of these studies were performed in whole hearts, further studies will reveal to what extent DOX primes or anti-primes cardiomyocytes to further pre-or post-MOMP apoptosis or to apoptosis susceptibility to cell death ligands.…”