Abstract 62: Selenoprotein P Promotes Vascular Smooth Muscle Cell Proliferation and Pulmonary Hypertension -A Possible Novel Therapeutic Target-

Abstract

Background: Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) is the main characteristics in pulmonary arterial hypertension (PAH); however, its mechanism still remains unclear. Methods & Results: To explore a novel therapeutic target in PAH, we performed a gene expression microarray screening using PASMCs from patients with PAH (PAH-PASMCs) and those from controls and found up-regulation of selenoprotein P (SeP) in PAH-PASMCs (>5-fold, P<0.01). SeP is a widely expressed extracellular protein, which transports selenium to whole body. Immunostaining showed strong expression of SeP in thickened pulmonary arteries (PA) in PAH. Chronic exposure of mice to hypoxia (O 2 10%) increased SeP expression in the lung. In PAH-PASMCs, hypoxia (O 2 2%, 24 hours) increased SeP expression compared with normoxic controls (O 2 21%) (1.6-fold, P<0.05). Treatment with human recombinant SeP (10μg/mL) up-regulated pro-proliferative genes, activated signals associated with cell-cycle, and increased PAH-PASMCs proliferation (P<0.05, n=8 each). SeP siRNA suppressed pro-proliferative signals with a resultant reduction in PASMCs proliferation. Next, SeP-deficient mice ( SeP -/- ) were exposed to hypoxia (O 2 10%) for 4 weeks, which resulted in suppression of right ventricular systolic pressure (RVSP), RV hypertrophy and PA remodeling compared with controls (all P<0.05, n=11 each). PASMCs proliferation was reduced in SeP -/- PASMCs compared with SeP +/+ PASMCs (P<0.05). SeP -/- PASMCs showed ERK1/2 inactivation, AMPK activation, and reduced secretion of pro-inflammatory cytokines. SMC-targeted deletion of SeP suppressed the development of hypoxia-induced PH compared with controls (all P<0.05, n=10). In contrast, liver-specific deletion of SeP did not affect the development of hypoxia-induced PH (all P>0.05, n=8-9). In the clinical study, serum SeP levels were significantly elevated in PAH patients (n=203) compared with controls (n=20) (P<0.001). Event-free curve revealed that high plasma SeP (≥27μg/ml) predicted poor outcome in PH patients (death or lung transplantation, P<0.01). Conclusions: These results indicate that SeP, especially in PASMCs, promotes PA remodeling, suggesting that it is a novel therapeutic target for PAH.