Abstract
Rationale Earlier studies have suggested an association between uric acid (UA) and pulmonary arterial hypertension (PAH) severity, but it remains unknown whether UA contributes to the disease pathogenesis.
Objectives To study the prognostic values of circulating UA at era of current management of PAH and investigate the role of UA in the pulmonary vascular remodelling.
Methods Serum UA levels were determined in idiopathic, heritable, or anorexigen PAH at baseline and first re-evaluation in the French PAH registry. We studied protein levels of xanthine oxidase (XO) and the URATv1 transporter 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).
Results High serum UA levels are associated with a poor prognosis at first follow-up, but not at baseline. Both the generating enzyme XO and URATv1 are upregulated in the wall of remodelled pulmonary arteries in iPAH patients and MCT and SuHx rats. High UA concentrations promote a mild increase in cell growth in iPAH PA-SMCs, but not in control PA-SMCs. Consistent with these observations, we demonstrate that oxonic acid-induced hyperuricemia did not aggravate MCT-induced PH in rats. Finally, we show that chronic treatments of MCT and SuHx rats with benzbromarone mildly attenuate pulmonary vascular remodelling.
Conclusions UA levels in iPAH patients is associated with impaired clinical and hemodynamic profile and might be used as a noninvasive indicator of clinical prognostic during follow-up. Our findings also indicate that metabolism of UA is disturbed in remodelled pulmonary vascular walls in both experimental and human PAH.
Footnotes
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Conflict of interest: Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;. Dr. Funke-Chambour reports grants from roche, grants and personal fees from Boehringer Ingelheim, outside the submitted work;.
Conflict of interest: Dr. Savale reports grants, personal fees and non-financial support from Actelion, personal fees and non-financial support from MSD, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from GSK, outside the submitted work;.
Conflict of interest: Dr. Akagi has nothing to disclose.
Conflict of interest: Dr. TU has nothing to disclose.
Conflict of interest: Dr. Cumont has nothing to disclose.
Conflict of interest: Dr. Thuillet has nothing to disclose.
Conflict of interest: Dr. Phan has nothing to disclose.
Conflict of interest: Dr. LE VELY has nothing to disclose.
Conflict of interest: Dr. BERREBEH has nothing to disclose.
Conflict of interest: Dr. HUERTAS has nothing to disclose.
Conflict of interest: Dr. JAIS reports grants and personal fees from Actelion, grants and personal fees from MSD, grants from Bayer, outside the submitted work;.
Conflict of interest: Dr. Cottin has nothing to disclose.
Conflict of interest: Dr. Chaouat has nothing to disclose.
Conflict of interest: Dr. TROMEUR has nothing to disclose.
Conflict of interest: Dr. Boucly reports personal fees and non-financial support from Actelion, personal fees from MSD, outside the submitted work;.
Conflict of interest: Dr. Jutant has nothing to disclose.
Conflict of interest: Dr. Mercier has nothing to disclose.
Conflict of interest: Dr. Fadel has nothing to disclose.
Conflict of interest: Dr. MONTANI reports grants and personal fees from Actelion, grants and personal fees from Bayer, personal fees from GSK, personal fees from Pfizer, personal fees from MSD, personal fees from Chiesi, outside the submitted work.
Conflict of interest: Dr. SITBON reports grants, personal fees and non-financial support from Actelion Pharmaceuticals, personal fees from Acceleron Pharmaceuticals, grants, personal fees and non-financial support from Bayer, grants, personal fees and non-financial support from MSD, grants from GlaxoSmithKline, personal fees from Gossamer Bio, personal fees from Ferrer, outside the submitted work;.
Conflict of interest: Dr. Humbert reports personal fees from Actelion, grants and personal fees from Bayer, grants and personal fees from GSK, personal fees from Merck, from United Therapeutics, personal fees from Acceleron, outside the submitted work.
Conflict of interest: Dr. Tamoura has nothing to disclose.
Conflict of interest: Dr. Guignabert has nothing to disclose.
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- Received February 15, 2020.
- Accepted December 20, 2020.
- ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
