Uric acid contributes to the progression of pulmonary hypertension in rodents and humans

Abstract

Uric acid (UA) has been identified as a prognostic factor in pulmonary arterial hypertension (PAH). However, the causal mechanisms linking elevated UA levels to the vascular remodeling of pulmonary arteries in experimental and human PAH are still unsettled. The aim of the study was to investigate the pathophysiological contribution of UA and its voltage-driven urate transporter 1 (URATv1) in experimental and human PAH. We examined serum UA levels in patients with idiopathic PAH and in rats with PH using two animal models (sugen-hypoxia and monocrotaline-induced PH). Expression patterns of xanthine oxidase (XO) and URATv1 were investigated in cultured human pulmonary artery-smooth muscle cells (PA-SMCs) as well as in whole lung homogenates from PAH patients and rats. Effect of hyperuricemia induced by oxionic acid on chronic hypoxia-induced PH was also studied. Finally, effects of an uricosuric agent, benzbromarone, on pulmonary vascular remodeling and experimental PH were determined. Idiopathic PAH patients and rats with PH exhibit increased levels of serum UA. We identified an overexpression XO and URATv1 in cultured iPAH PA-SMCs as well as in the smooth muscle from remodeled pulmonary arteries of rodents and humans. We also found that UA promotes the proliferation of cultured human PA-SMCs, a phenomenon abolished with benzbromarone. Whereas hyperuricemia induced by oxionic acid increases the susceptibility to chronic hypoxia-induced PH, benzbroramone prevents and reverses established PH in the MCT and SuHX rat models. Our results reveal a direct role of UA in PA-SMC accumulation in experimental and human PAH, highlighting the potential interests of uricosuric agent in these severe conditions.