School of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
INSERM UMR_S 999 "Pulmonary Hypertension: Pathophysiology and Novel Therapies", Hôpital Marie Lannelongue, Le Plessis-Robinson, France.
Eur Respir J. 2021 Aug 5;58(2). doi: 10.1183/13993003.00332-2020. Print 2021 Aug.
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.
先前的研究表明尿酸（UA）与肺动脉高压（PAH）的严重程度之间存在关联，但尚不清楚 UA 是否有助于疾病的发病机制。本研究旨在确定当前 PAH 管理时代循环 UA 的预后价值，并探讨 UA 在肺血管重构中的作用。在法国肺动脉高压网络中，在特发性、遗传性或厌食性 PAH 患者的基线和首次重新评估时测定血清 UA 水平。我们研究了对照和 PAH 患者以及马兜铃酸（MCT）和苏根/低氧（SuHx）大鼠肺中黄嘌呤氧化酶（XO）和电压驱动的尿酸转运蛋白 1（URATv1）的蛋白水平。使用人肺动脉平滑肌细胞（PA-SMC）和两种肺动脉高压（PH）动物模型进行了功能研究。首次随访时的高血清 UA 水平，但不是基线时的高血清 UA 水平与预后不良相关。在特发性 PAH 患者和 MCT 和 SuHx 大鼠的重构肺血管壁中，生成酶 XO 和 URATv1 均上调。高 UA 浓度可促进特发性 PAH PA-SMC 轻度增加细胞生长，但不能促进对照 PA-SMC 生长。与这些观察结果一致，oxonic 酸诱导的高尿酸血症并未加重大鼠 MCT 诱导的 PH。最后，用苯溴马隆对 MCT 和 SuHx 大鼠进行慢性治疗可轻度减轻肺血管重构。特发性 PAH 患者的 UA 水平与受损的临床和血液动力学特征相关，可作为随访期间临床预后的非侵入性指标。我们的研究结果还表明，UA 代谢在实验和人类 PAH 重构的肺血管壁中受到干扰。
