The Apoptotic Regulatory Protein ARC (Apoptosis Repressor with Caspase Recruitment Domain) Prevents Oxidant Stress-mediated Cell Death by Preserving Mitochondrial Function

Abstract

ARC is an apoptotic regulatory protein expressed almost exclusively in myogenic cells. It contains a caspase recruitment domain (CARD) through which it has been shown to block the activation of some initiator caspases. Because ARC also blocks caspase-independent events associated with apoptosis, such as hypoxia-induced cytochrome c release, we examined its role in cell death triggered by exposure to hydrogen peroxide (H 2 O 2 ) in the myogenic cell line, H9c2. Cell death in this model was caspase-independent and characterized by dose-dependent reduction in ARC expression accompanied by disruption of the mitochondrial membrane potential (⌬ m ) and loss of plasma membrane integrity, typical of necrotic cell death. Ectopic expression of ARC prevented both H 2 O 2 -induced mitochondrial dysfunction and cell death without affecting the stress kinase response, suggesting that ARCs protective effects were downstream of early signaling events and not due to quenching of H 2 O 2 . ARC was also effective in blocking H 2 O 2 -induced loss of membrane integrity and/or disruption of ⌬ m in two human cell lines in which it is not normally expressed. These results demonstrate that, in addition to its ability to block caspase-dependent and -independent events in apoptosis, ARC also prevents necrosis-like cell death via the preservation of mitochondrial function.

Autophagic program is regulated by miR-325

“…It can interact with Fas, FADD and Bax, 33,38 inhibit cytochrome c release 39 and maintain mitochondrial membrane potential. 40,41 These lines of evidence suggest that ARC is a critical factor for maintaining the cellular function. Our present work reveals that ARC participates in the regulation of autophagy to maintain the equilibrium between autophagic cell death and cell survival.…”

A novel protective effect of erythropoietin in the infarcted heart

“…On the one hand, anemia has been associated with higher mortality in cardiac patients and, by stimulating hematopoiesis, EPO may increase O 2 delivery to the myocardium, resulting in some functional benefit (24,29). On the other hand, correction of hematocrit may not translate into therapeutic gains.…”

Transcription Factor Foxo3a Prevents Apoptosis by Regulating Calcium through the Apoptosis Repressor with Caspase Recruitment Domain

“…ARC transgenic mice exhibit less myocardial infarction sizes (56), whereas ARC knock-out mice demonstrate accelerated myocardial infarction (47). ARC levels are significantly decreased in cardiomyocytes upon treatment with hydrogen peroxide and hypoxia (20,23). Furthermore, ARC levels are reduced upon heart failure (47) or ischemia (57).…”

“…Further studies revealed that ARC also may elicit its anti-apoptotic function by other means. It can interact with Fas, FADD, and Bax (20,21), inhibit cytochrome c release (22), and maintain mitochondrial membrane potential (23,24). Despite ARC's abundant expression and blocking apoptosis induced by either intrinsic or extrinsic stimulus, cardiomyocytes still undergo apoptosis under pathological conditions such as oxidative stress (23,25) and hypoxia (26 -28).…”