BackgroundRecent studies have demonstrated that uric acid (UA) enhances arginase activity, resulting in decreased NO in endothelial cells. However, the role of lung UA in pulmonary arterial hypertension (PAH) remains uncertain. We hypothesized that increased lung UA level contributes to the progression of PAH.Methods and ResultsIn cultured human pulmonary arterial endothelial cells, voltage‐driven urate transporter 1 (URATv1) gene expression was detected, and treatment with UA increased arginase activity. In perfused lung preparations of VEGF receptor blocker (SU5416)/hypoxia/normoxia‐induced PAH model rats, addition of UA induced a greater pressure response than that seen in the control and decreased lung cGMP level. UA‐induced pressor responses were abolished by benzbromarone, a UA transporter inhibitor, or L‐norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by administering 2% oxonic acid significantly increased lung UA level and induced greater elevation of right ventricular systolic pressure with exacerbation of occlusive neointimal lesions in small pulmonary arteries, compared with nonhyperuricemic PAH rats. Administration of benzbromarone to hyperuricemic PAH rats significantly reduced lung UA levels without changing XOR (xanthine oxidoreductase) activity, and attenuated right ventricular systolic pressure increase and occlusive lesion development. Topiroxostat, a XOR inhibitor, significantly reduced lung XOR activity in PAH rats, with no effects on increase in right ventricular systolic pressure, arterial elastance, and occlusive lesions. XOR‐knockout had no effects on right ventricular systolic pressure increase and arteriolar muscularization in hypoxia‐exposed mice.ConclusionsIncreased lung UA per se deteriorated PAH, whereas XOR had little impact. The mechanism of increased lung UA may be a novel therapeutic target for PAH complicated with hyperuricemia.

中文翻译：

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增加的肺尿酸恶化肺动脉高压

背景最近的研究表明，尿酸 (UA) 可增强精氨酸酶的活性，导致内皮细胞中的 NO 减少。然而，肺 UA 在肺动脉高压 (PAH) 中的作用仍不确定。我们假设增加的肺 UA 水平有助于 PAH 的进展。方法和结果在培养的人肺动脉内皮细胞中，检测到电压驱动的尿酸盐转运蛋白 1 (URATv1) 基因表达，并且用 UA 治疗增加了精氨酸酶活性。在 VEGF 受体阻滞剂 (SU5416)/缺氧/常氧诱导的 PAH 模型大鼠的肺灌注制剂中，与对照组相比，添加 UA 诱导了更大的压力反应，并降低了肺 cGMP 水平。UA 诱导的升压反应被 UA 转运蛋白抑制剂苯溴马隆或精氨酸酶抑制剂 L-正缬氨酸消除。在 PAH 模型大鼠中，与非高尿酸血症的 PAH 大鼠相比，通过施用 2% 含氧酸诱导的高尿酸血症显着增加了肺 UA 水平，并诱导了右心室收缩压的更大升高，并加剧了小肺动脉中的闭塞性新内膜病变。对高尿酸血症 PAH 大鼠施用苯溴马隆可显着降低肺 UA 水平，而不会改变 XOR（黄嘌呤氧化还原酶）活性，并减轻右心室收缩压升高和闭塞性病变发展。托吡司他是一种 XOR 抑制剂，可显着降低 PAH 大鼠的肺 XOR 活性，但对右心室收缩压、动脉弹性和闭塞性病变的增加没有影响。XOR 基因敲除对缺氧小鼠的右心室收缩压升高和小动脉肌化没有影响。结论肺 UA 本身的增加使 PAH 恶化，而 XOR 几乎没有影响。肺UA增加的机制可能是PAH合并高尿酸血症的新治疗靶点。