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 (Egln1Tie2Cre, 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 Egln1Tie2Cre 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 Egln1Tie2Cre mice. Genetic restoration of Cav1 expression in Egln1Tie2Cre 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.
| Original language | English (US) |
|---|---|
| Article number | 2102643 |
| Journal | European Respiratory Journal |
| Volume | 60 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 1 2022 |
Funding
Support statement: This work was supported in part by National Institutes of Health (NIH) (grants R01HL133951, R01HL140409, R01HL148810 and R01HL164014) to Y-Y. Zhao, and by NIH (R00HL13827 and R01HL158596), AHA Career Development Award (20CDA35310084), ATS Foundation Pulmonary Hypertension Association Research Fellowship, Arizona Biomedical Research Cente (ADHS18-198871) and the University of Arizona departmental start-up funding to Z. Dai. Funding information for this article has been deposited with the Crossref Funder Registry. We greatly appreciate William C. Sessa from the Departments of Pharmacology and Medicine at Yale School of Medicine for his generosity in providing us with the Cav1Tg mice. This work was supported in part by National Institutes of Health (NIH) (grants R01HL133951, R01HL140409, R01HL148810 and R01HL164014) to Y-Y. Zhao, and by NIH (R00HL13827 and R01HL158596), AHA Career Development Award (20CDA35310084), ATS Foundation Pulmonary Hypertension Association Research Fellowship, Arizona Biomedical Research Cente (ADHS18-198871) and the University of Arizona departmental start-up funding to Z. Dai. Funding information for this article has been deposited with the Crossref Funder Registry.
ASJC Scopus subject areas
- Pulmonary and Respiratory Medicine
