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Pulmonary primary oxysterol and bile acid synthesis as a predictor of outcomes in pulmonary arterial hypertension.
- Source :
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BioRxiv : the preprint server for biology [bioRxiv] 2024 Jan 23. Date of Electronic Publication: 2024 Jan 23. - Publication Year :
- 2024
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Abstract
- Pulmonary arterial hypertension (PAH) is a rare and fatal vascular disease with heterogeneous clinical manifestations. To date, molecular determinants underlying the development of PAH and related outcomes remain poorly understood. Herein, we identify pulmonary primary oxysterol and bile acid synthesis (PPOBAS) as a previously unrecognized pathway central to PAH pathophysiology. Mass spectrometry analysis of 2,756 individuals across five independent studies revealed 51 distinct circulating metabolites that predicted PAH-related mortality and were enriched within the PPOBAS pathway. Across independent single-center PAH studies, PPOBAS pathway metabolites were also associated with multiple cardiopulmonary measures of PAH-specific pathophysiology. Furthermore, PPOBAS metabolites were found to be increased in human and rodent PAH lung tissue and specifically produced by pulmonary endothelial cells, consistent with pulmonary origin. Finally, a poly-metabolite risk score comprising 13 PPOBAS molecules was found to not only predict PAH-related mortality but also outperform current clinical risk scores. This work identifies PPOBAS as specifically altered within PAH and establishes needed prognostic biomarkers for guiding therapy in PAH.<br />Competing Interests: Competing interests: None of the authors have any potential conflicts of interest relative to the study. S.Y.C. has served as a consultant to United Therapeutics, Janssen, and Merck; S.Y.C. has held research grants from Bayer and United Therapeutics. S.Y.C. is a director, officer, and shareholder of Synhale Therapeutics. S.Y.C. and L.D.H. have submitted patent applications regarding metabolism in pulmonary hypertension. N.H.K. has served as consultant for Bayer, Janssen, Merck, United Therapeutics and has received lecture fees for Bayer, Janssen. N.H.K. has received research support from Acceleron, Eiger, Gossamer Bio, Lung Biotechnology, SoniVie. A.M.B. served as a consultant to Biogen. J.D.W, T.L., and M.J. currently hold positions and equity in Sapient Bioanalytics, LLC, for work unrelated to the current paper. V.S. has had research collaboration with Bayer Ltd (outside the present study). J.T is a stockholder of Orion Pharma.
Details
- Language :
- English
- Database :
- MEDLINE
- Journal :
- BioRxiv : the preprint server for biology
- Accession number :
- 38328113
- Full Text :
- https://doi.org/10.1101/2024.01.20.576474