A Critical Role for the Protein Apoptosis Repressor With Caspase Recruitment Domain in Hypoxia-Induced Pulmonary Hypertension

Abstract

Background Pulmonary hypertension (PH) is a lethal syndrome associated with the pathogenic remodeling of the pulmonary vasculature and the emergence of apoptosis-resistant cells. ARC (Apoptosis Repressor with Caspase Recruitment Domain) is an inhibitor of multiple forms of cell death known to be abundantly expressed in striated muscle. We show for the first time that ARC is expressed in arterial smooth muscle cells of the pulmonary vasculature and is markedly up-regulated in several experimental models of PH. In this study, we test the hypothesis that ARC expression is essential for the development of chronic hypoxia-induced PH. Methods and Results Experiments in which cells or mice were rendered ARC-deficient revealed that ARC not only protected pulmonary arterial smooth muscle cells from hypoxia-induced death, but also facilitated growth factor-induced proliferation and hypertrophy and hypoxia-induced down-regulation of selective voltage-gated potassium channels, the latter a hallmark of the syndrome in humans. Moreover, ARC-deficient mice exhibited diminished vascular remodeling, increased apoptosis, and decreased proliferation in response to chronic hypoxia, resulting in marked protection from PH in vivo. Patients with PH have significantly increased ARC expression not only in remodeled vessels but also in the lumen-occluding lesions associated with severe disease. Conclusions These data show that ARC, previously unlinked to pulmonary hypertension, is a critical determinant of vascular remodeling in this syndrome.

The Apoptosis Repressor with a CARD Domain (ARC) Gene Is a Direct Hypoxia-Inducible Factor 1 Target Gene and Promotes Survival and Proliferation of VHL-Deficient Renal Cancer Cells

“…Unlike our observations in a variety of human cancer cell types, hypoxia treatment of rat H9C2 cardiomyocytes and ventricular myocytes led to decreased ARC levels in a manner that correlated with the induction of apoptosis and/or necrosis (41). On the other hand, in the recent report by Zaiman et al, ARC was shown to be induced by hypoxia in isolated rat pulmonary arterial smooth muscle cells (44). Interestingly, the putative HIF1␣ binding site identified in our study appears to be conserved in primates but is not present in the mouse or rat ARC promoter (Fig.…”

Apoptosis Inhibitor ARC Promotes Breast Tumorigenesis, Metastasis, and Chemoresistance

“…2E). This proliferation function of ARC has not been previously described, although we have recently observed that ARC knockdown/knockout also impairs the proliferation of benign MCF-10A breast epithelial cells (unpublished data, C. Medina-Ramirez and R. Kitsis) and hypoxic pulmonary arterial smooth muscle cells in vivo (27). The mechanism of ARC-induced cellular proliferation is not known.…”

“…We generated mice with generalized deletion both alleles of nol3 (encompassing the entire open reading frame of ARC) and backcrossed them onto a C57Bl/6 background as described (27). The absence of ARC protein in hearts of nol3 −/− mice is shown in Supplementary Fig.…”

Mechanisms of Cell Death in Heart Disease

“…55 ARC expression was initially believed to be limited to cardiac and skeletal myocytes and neurons, but recent data shows that is also induced at high levels in cancer cells 56-58 and hypoxic pulmonary artery smooth muscle cells in vivo . 59 …”