Abstract
Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension (PAH). However, the role of nitrative stress in the pathogenesis of obliterative vascular remolding and severe PAH remains largely unclear. Our recent studies identified a novel mouse model (Egln1Tie2Cre, Egln1 encoding prolyl hydroxylase 2 [PHD2]) with obliterative vascular remodeling and right heart failure, which provides us an excellent model to study the role of nitrative stress in obliterative vascular remodeling. Here we show that nitrative stress was markedly elevated whereas endothelial Caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1Tie2Cre mice. ROS scavenger manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) treatment inhibited obliterative pulmonary vascular remodeling and suppressed severe PAH in Egln1Tie2Cre mice. Genetic restoration of endothelial Cav1 expression in Egln1Tie2Cre mice normalized nitrative stress, reduced PAH and improved right heart function. These data suggest that suppression of endothelial Cav1 expression secondary to PHD2 deficiency augments nitrative stress, which contributes to obliterative vascular remodeling and severe PAH. Thus, ROS scavenger might have great therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.
Competing Interest Statement
The authors have declared no competing interest.
