Endothelial PHD2 deficiency induces nitrative stress via suppression of caveolin-1 in pulmonary hypertension. Issue 6 (22nd December 2022)

• Record Type: Journal Article
• 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
• Is Part Of: European respiratory journal. Volume 60:Issue 6(2022)
• Publication Date: 2022-12-22
• Subjects: Respiratory organs -- Diseases -- Periodicals; Respiration -- Periodicals; 616.2
• DOI: 10.1183/13993003.02643-2021
• Languages: English
• ISSNs: 0903-1936

Abstract

Background: 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. Method: Our recently identified novel mouse model ( Egln1 Tie2Cre, Egln1 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. Results: Nitrative stress was markedly elevated whereas endothelial caveolin-1 (Cav1) expression was suppressed in the lungs of Egln1 Tie2Cre mice. Treatment with a superoxide dismutase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride or endothelial Nos3 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 Egln1 Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1 Tie2Cre mice normalised nitrative stress, reduced pulmonary hypertension and improved right heart function. Conclusion: 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. Endothelial PHD2 deficiency decreases caveolin-1 expression leading to augmented nitrative stress, which contributes to obliterative pulmonary vascular remodelling and severe pulmonary hypertension https://bit.ly/3yw48zm