Serum and pulmonary uric acid in pulmonary arterial hypertension

Abstract

RationaleEarlier 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.ObjectivesTo 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.MethodsSerum 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).ResultsHigh 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.ConclusionsUA 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.

The Prognostic Impact of Serum Uric Acid on Disease Severity and 5-Year Mortality in Patients With Idiopathic Pulmonary Artery Hypertension

“…Previous experimental studies also demonstrated that UA could stimulate smooth muscle cell proliferation by increasing angiotensin-II production, cyclooxygenase 2, endothelin-1, platelet-derived growth factor, ROS, and activating different pathways including extracellular signal-regulated protein kinases and p38 kinase pathway, NF-κB and c-Jun/AP-1 pathway ( 24 , 29 , 30 ). Further, in a recent in vivo experimental study, it was reported that local UA production is observed in the pulmonary vasculature of patients with IPAH, and higher UA concentrations could also promote cell growth and ROS production in PA-SMCs ( 31 ). Additionally, in two animal models of severe PH, local UA production is increased ( 31 ).…”

“…Further, in a recent in vivo experimental study, it was reported that local UA production is observed in the pulmonary vasculature of patients with IPAH, and higher UA concentrations could also promote cell growth and ROS production in PA-SMCs ( 31 ). Additionally, in two animal models of severe PH, local UA production is increased ( 31 ). In this regard, these findings could provide some plausible mechanisms that UA has a direct contributory and pathogenic role in the progression of PH, which could also impose devastating effects on the prognosis of patients with IPAH.…”

Prognostic Significance of Uric Acid in Patients with Obstructive and Nonobstructive Coronary Artery Disease Undergoing D-SPECT

“…The association of SUA levels with clinical outcomes has been extensively studied in various settings and yielded conflicting results. [17][18][19][20] In the Progetto Ipertensione Umbria Monitoraggio Ambulatoriale (PIUMA) registry, SUA was independently associated with adverse cardiovascular events in patients with essential hypertension. 21 Differently, in a large population-based observational study with a median follow-up of nearly 6 years, Cheong et al demonstrated that both men and women in the highest quintile of SUA levels were not challenged by higher cardiovascular mortality when compared to the middle SUA quintile after multivariable adjustment.…”

Pulmonary hypertension associated with neurofibromatosis type 2

“…Immunofluorescent staining and microscopy: Immunofluorescent staining for NF2 (1:100; sc-55575 from Santa Cruz), α-SMA (1:200; sc-32251 from Santa Cruz), and vWF (1:200; A0082 from DAKO) were performed in lung paraffin sections as previously described 11,12 . Briefly, lung sections (5μm of thickness) were deparaffinized and incubated with the antigen retrieval buffer.…”

“…Western Immunoblot: Cells were homogenized and sonicated in PBS containing protease and phosphatase inhibitors (Sigma-Aldrich). Fifty µg of protein extract were used to detect NF2 (sc-55575; 1:200) by SDS-PAGE as previously described 11,12…”