Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension

• Published in: The European respiratory journal Vol. 60; no. 6; p. 2102643
• Main Authors: Liu, Bin, Peng, Yi, Yi, Dan, Machireddy, Narsa, Dong, Daoyin, Ramirez, Karina, Dai, Jingbo, Vanderpool, Rebecca, Zhu, Maggie M, Dai, Zhiyu, Zhao, You-Yang
• Format: Journal Article
• Language: English
• Published: England European Respiratory Society 01.12.2022
• Subjects: Animals; Caveolin 1 - genetics; Caveolin 1 - metabolism; Disease Models, Animal; Humans; Hypoxia-Inducible Factor-Proline Dioxygenases - genetics; Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism; Lung - metabolism; Mice; Nitrosative Stress - genetics; Original s; Pulmonary Arterial Hypertension - genetics; Pulmonary Arterial Hypertension - metabolism; Reactive Nitrogen Species - metabolism; Reactive Oxygen Species - metabolism; Vascular Remodeling - genetics
• ISSN: 0903-1936; 1399-3003
• DOI: 10.1183/13993003.02643-2021

Nitrative stress is a characteristic feature of the pathology of human pulmonary arterial hypertension. However, the role of nitrative stress in the pathogenesis of obliterative vascular remodelling and severe pulmonary arterial hypertension remains largely unclear. Our recently identified novel mouse model ( encoding prolyl hydroxylase 2 (PHD2)) has obliterative vascular remodelling and right heart failure, making it an excellent model to use in this study to examine the role of nitrative stress in obliterative vascular remodelling. Nitrative stress was markedly elevated whereas endothelial caveolin-1 (Cav1) expression was suppressed in the lungs of mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride or endothelial knockdown using endothelial cell-targeted nanoparticle delivery of CRISPR-Cas9/guide RNA plasmid DNA inhibited obliterative pulmonary vascular remodelling and attenuated severe pulmonary hypertension in mice. Genetic restoration of Cav1 expression in mice normalised nitrative stress, reduced pulmonary hypertension and improved right heart function. These data suggest that suppression of Cav1 expression secondary to PHD2 deficiency augments nitrative stress through endothelial nitric oxide synthase activation, which contributes to obliterative vascular remodelling and severe pulmonary hypertension. Thus, a reactive oxygen/nitrogen species scavenger might have therapeutic potential for the inhibition of obliterative vascular remodelling and severe pulmonary arterial hypertension.