Abstract
Previous studies have suggested an association between uric acid (UA) and the severity of pulmonary arterial hypertension (PAH), but it is unknown whether UA contributes to disease pathogenesis.
The aim of this study was to determine the prognostic value of circulating UA in the era of current management of PAH and to investigate the role of UA in pulmonary vascular remodelling.
Serum UA levels were determined in idiopathic, heritable or anorexigen PAH at baseline and first re-evaluation in the French Pulmonary Hypertension Network. We studied protein levels of xanthine oxidase (XO) and the voltage-driven urate transporter 1 (URATv1) in lungs of control and PAH patients and of monocrotaline (MCT) and Sugen/hypoxia (SuHx) rats. Functional studies were performed using human pulmonary artery smooth muscle cells (PA-SMCs) and two animal models of pulmonary hypertension (PH).
High serum UA levels at first follow-up, but not at baseline, were associated with a poor prognosis. Both the generating enzyme XO and URATv1 were upregulated in the wall of remodelled pulmonary arteries in idiopathic PAH patients and MCT and SuHx rats. High UA concentrations promoted a mild increase in cell growth in idiopathic PAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, oxonic acid-induced hyperuricaemia did not aggravate MCT-induced PH in rats. Finally, chronic treatment of MCT and SuHx rats with benzbromarone mildly attenuated pulmonary vascular remodelling.
UA levels in idiopathic PAH patients were associated with an impaired clinical and haemodynamic profile and might be used as a non-invasive indicator of clinical prognosis during follow-up. Our findings also indicate that UA metabolism is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.
Abstract
Uric acid (UA) level is associated with poor prognosis in PAH. Local UA production is increased in the remodelled pulmonary vasculature, and inhibition of UA incorporation in PA-SMCs reduces their proliferation and mildly reduces experimental PH. https://bit.ly/2Ll5qXM
Footnotes
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Conflict of interest: L. Savale reports grants, personal fees and non-financial support from Actelion and GSK, and personal fees and non-financial support from MSD and Bayer, outside the submitted work.
Conflict of interest: S. Akagi has nothing to disclose.
Conflict of interest: L. Tu has nothing to disclose.
Conflict of interest: A. Cumont has nothing to disclose.
Conflict of interest: R. Thuillet has nothing to disclose.
Conflict of interest: C. Phan has nothing to disclose.
Conflict of interest: B. Le Vely has nothing to disclose.
Conflict of interest: N. Berrebeh has nothing to disclose.
Conflict of interest: A. Huertas has nothing to disclose.
Conflict of interest: X. Jaïs reports grants and personal fees from Actelion and MSD, grants from Bayer, outside the submitted work.
Conflict of interest: V. Cottin has nothing to disclose.
Conflict of interest: A. Chaouat has nothing to disclose.
Conflict of interest: C. Tromeur has nothing to disclose.
Conflict of interest: A. Boucly reports personal fees and non-financial support from Actelion and personal fees from MSD, outside the submitted work.
Conflict of interest: E.M. Jutant has nothing to disclose.
Conflict of interest: O. Mercier has nothing to disclose.
Conflict of interest: E. Fadel has nothing to disclose.
Conflict of interest: D. Montani reports grants and personal fees from Actelion and Bayer, and personal fees from GSK, Pfizer, MSD and Chiesi, outside the submitted work.
Conflict of interest: O. Sitbon reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, Bayer and MSD, personal fees from Acceleron Pharmaceuticals, Gossamer Bio and Ferrer, and grants from GlaxoSmithKline, outside the submitted work.
Conflict of interest: M. Humbert reports grants and personal fees from Bayer and GSK, and personal fees from Actelion, Merck, United Therapeutics and Acceleron, outside the submitted work.
Conflict of interest: Y. Tamura has nothing to disclose.
Conflict of interest: C. Guignabert has nothing to disclose.
Support statement: This research was supported by grants from the French National Institute for Health and Medical Research (INSERM), the University Paris-Saclay, the Marie Lannelongue Hospital, the French National Agency for Research (ANR) grant number ANR-16-CE17-0014 (TAMIRAH) and ANR-18-RHUS-0006 (RHU DESTINATION 2024), the Fondation de la Recherche Médicale (FRM) grant number DEQ20150331712 (Equipe FRM 2015), and in part by the Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), the Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, Centre de Référence de l'Hypertension Pulmonaire Sévère, the LabEx LERMIT (grant number ANR-10-LABX-0033), the French PAH patient association (HTAP France) and the French Fonds de Dotation “Recherche en Santé Respiratoire” – (FRSR) – Fondation du Souffle (FdS). N. Berrebeh is supported by the Ile-de-France Regional Council with a doctoral contract (ARDoC 2018). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received February 15, 2020.
- Accepted December 20, 2020.
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