Abstract 15511: Apoptosis Repressor woth CARD is a Smooth Muscle Cell Survival Factor that Promotes Pulmonary Arterial Hypertension
Vascular remodeling is regulated by both growth-promoting and suppressing pathways. Pulmonary artery smooth muscle cells (PASMCs) contribute to the structural remodeling of the lung vasculature seen in pulmonary arterial hypertension (PAH). ARC (Apoptosis Repressor with Caspase Recruitment Domain) is a death repressor that we have shown to be expressed in PASMCs and to be upregulated in animal models of PAH, including chronic exposure to hypoxia (CH). Importantly, while isolated PASMCs survive exposure to CH, PASMCs made ARC-deficient by shRNA-mediated post-transcriptional gene silencing die. As a survival factor for PASMCs, we hypothesized that ARC promotes vascular remodeling and the development of CH-induced PAH. To test this, we used an intact mouse model of CH-induced PAH (3 weeks at 10% FIO2) in which the gene that encodes ARC (Nol3) was deleted in the germline. No significant hemodynamic differences were seen in the hemodynamic profile of wild type (WT) and knockout (KO) mice in room air (normoxia, N) (Table, column 1 vs 3). In WT mice, CH led to increased PASMC proliferation and muscularization of the pulmonary vasculature, as well as marked increases in pulmonary vascular resistance (PVR), right ventricular end-systolic pressure (RVESP), mean pulmonary arterial pressure (mPAP), and marked decreases in the contractility index (dP/dt/IP) and cardiac output (CO) (Table. column 2 vs 1). Relative to WT-CH mice, the responses of the KO mice to CH were severely attenuated. PASMC proliferation decreased (−64.2±7.6%), PASMC apoptosis increased (−45.2±6.8%), and muscularization of distal arterioles was markedly suppressed (−68±7.3%). Increases in PVR, RVESP, and mPAP were 70.6%, 44.6 % and 53.9% lower in KO-CH mice, while dP/dt/IP increased 30.6% and CO 85.7% of KO-N levels. These data show that ARC contributes to the development of CH-induced PAH in the mouse, potentially but not necessarily limited to its role as a survival factor for PASMCs.
- © 2010 by American Heart Association, Inc.