Uric acid causes excessive pulmonary arterial smooth muscle cell proliferationviaURATv1 upregulation in pulmonary arterial hypertension

Background: Increased levels of uric acid (UA) in serum of patients with pulmonary arterial hypertension (PAH) are associated with severity and clinical outcomes. However, the pathophysiological contribution of UA in pulmonary vascular remodeling associated with PAH remains unknown. Objectives: To study pathophysiological roles of UA in experimental and human PAH and to evaluate the translational potential of benzbromarone, an inhibitor against UA transporter URATv1. Methods: We examined serum UA level and the expression pattern of URATv1 in cultured pulmonary artery smooth muscle cells (PA-SMCs) and in lungs of 10 controls (CTR) and 10 patients with idiopathic PAH (IPAH). In addition, the preventive and curative effects of benzbromarone were tested in two experimental models of pulmonary hypertension (PH). Results: In IPAH, we found elevated levels of serum UA and a strong immunoreactivity for URATv1 in the media of remodeled pulmonary arteries and cultured PA-SMCs of IPAH patients when compared with controls. These findings were also replicated in vivo with high in situ levels of URATv1 in PA-SMCs of PH rats. Consistent with these findings, we also demonstrated in vitro that the upregulation of URATv1 contributes to an increased proliferative response to UA in IPAH PA-SMCs when compared with CTR cells, a phenomenon abolished with benzbromarone. Finally, we found that benzbromarone partially prevented and reversed established PH in the monocrotaline and SU5416+hypoxia rat models. Conclusions: Our results support the possibility that the blockade of UA transporter may represent promising novel approaches for treatment of PAH.