Abstract 12497: Diminished Cavolin-1 Expression and Augmented Nitrative Stress Secondary to Prolyl-4 Hydroxylase 2 Deficiency Contribute to Obliterative Vascular Remodeling and Severe Pulmonary Arterial Hypertension

Abstract

Background: Pulmonary arterial hypertension (PAH) is a progressive disease characterized by increased pulmonary vascular resistance and vascular remodeling. Our recent study for the first time demonstrated that loss of prolyl-4 hydroxylase 2 (PHD2) in endothelial cells and bone marrow cells in mice induces severe PAH with obliterative pulmonary vascular remodeling and plexiform-like lesions recapitulating clinical PAH. However, it is unclear whether nitrative stress is involved in the pathogenesis of PAH in this mouse model. Methods: Endothelial-specific Egln1 (encoding PHD2) disruption ( Egln1 Tie2 ), Egln1 and Hif2a double knockout ( EH2 ) mice were generated. Western blotting and immunostaining were performed to quantify nitration stress and caveolin-1 expression in WT, Egln1 Tie2 and EH2 mice. MnTMPyP (a superoxide scavenger) were administrated to Egln1 Tie2 mice. Right ventricular systolic pressure (RVSP) and RV/(LV+S) ratio, indicator of RV hypertrophy, were measured. Medial thickness and muscularization of distal pulmonary arteries were assessed by histological examination. Human lung microvascular endothelial cells (HLMECs) was cultured. Results: Nitrotyrosine was increased in Egln1 Tie2 mice and normalized in EH2 mice. MnTMPyP treatment inhibited RVSP increase and RV hypertrophy, and decreased medial thickness and muscularization of distal pulmonary arterials in Egln1 Tie2 mice. Mechanistically, endothelial Caveolin-1 expression was decreased in Egln1 Tie2 mice and normalized in EH2 mice. Consistently, PHD inhibitor DMOG decreased Caveolin-1 expression in HLMECs. Conclusion: These data show that loss of endothelial PHD2 suppresses Caveolin-1 expression in a HIF-2α dependent manner. Decrease of Caveolin-1 expression and resultant activation of nitration stress contribute to the severe vascular remodeling and PAH in Egln1 Tie2 mice. Thus, targeting nitrative stress is a novel therapeutic strategy for the treatment of PAH.