Raptor activation by aldosterone promotes apoptosis resistance in pulmonary artery smooth muscle cells to modulate adverse pulmonary vascular remodeling in pulmonary arterial hypertension

Abstract

In pulmonary arterial hypertension (PAH), hyperaldosteronism (ALDO) is associated with adverse vascular remodeling typified by pulmonary artery smooth muscle cell (PSMC) proliferation and apoptosis resistance. Raptor activation induces PSMC growth and inhibits apoptosis; however, the role of ALDO‐Raptor signaling in PAH vascular remodeling is unknown. We, therefore, treated human PSMCs with ALDO (10−7 mol/L) or vehicle (V) for 1 h. Compared to V‐treated cells, ALDO increased P‐raptor (Ser792) expression by 197% (p<0.05) without affecting total raptor levels. ALDO exposure promoted apoptosis resistance in PSMCs; in cells treated with ALDO prior to hydrogen peroxide (1 mM) exposure for 24 h, ALDO decreased apoptosis by 60% (p=0.02) as determined by an apoptosis ELISA. Next, we assessed the effect of ALDO‐raptor on vessel remodeling in the monocrotaline (MCT)‐induced PAH rat model. Compared to V‐treated rats, immunohistochemistry of pulmonary arterioles from PAH rats demonstrated an 85% (p<0.05) increase in levels of P‐p70S6K (Thr389), which mediates raptor‐dependent cell proliferation. ALDO antagonism with spironolactone (25 mg/kg/d) in PAH rats decreased P‐p70S6K by 49% (p<0.02) and increased vessel lumen area by 268% (p<0.05) compared to untreated PAH rats. Together, these data suggest that ALDO‐raptor signaling in PSMCs is a novel mechanism to modulate vascular remodeling in PAH. Funding: NIH/BHF.