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 [ 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 expression was suppressed in the lungs of mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-... More
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 [ 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 expression was suppressed in the lungs of mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTmPyP) or endothelial knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/gRNA plasmid DNA inhibited obliterative pulmonary vascular remodeling and attenuated severe PH in mice. Genetic restoration of Cav1 expression in mice normalized nitrative stress, reduced PH and improved right heart function. These data suggest that suppression of Caveolin-1 expression secondary to PHD2 deficiency augments nitrative stress through eNOS activation, which contributes to obliterative vascular remodeling and severe PH. Thus, reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodeling and severe PAH.
