Hyperuricemia impaired nitric oxide bioavailablity and deteriorated pulmonary arterial hypertension via a uric acid transporter, URATv1 in xanthine oxidoreductase (XOR)-independent manner

Background Hyperuricemia occurs in approximately 80% in patients with pulmonary arterial hypertension (PAH) and is positively correlated with pulmonary arterial pressure (PAP). It has been reported that uric acid (UA) reduced endothelium derived nitric oxide (NO) production in porcine pulmonary arterial endothelial cells (PAEC). However, the effects of UA and xanthine oxidoreductase (XOR), catalytic enzyme of UA, on the development of PAH have not been fully elucidated. Purpose We examined the followings; (1) the effects of hyperuricemia on the endothelial function and the development of PAH in rats (2) the therapeutic effects of UA transporter inhibitor on PAH in rats, and (3) the role of XOR in PAH in mice. Methods We used normal and 5-wk Sugen5416/Hypoxia/Normoxia-exposed (SU/Hx/Nx) rats. Gene expression levels of URATv1, a UA transporter, were measured by RT-PCR. We determined the isometric tension of PA rings isolated from normal rats. The study with the isolated perfused lung preparation was performed in SU/HX/Nx rats. To investigate the chronic effect of UA on the development of PAH, hyperuricemia was induced by the administration of 2% oxonic acid (OA) in diet for 6-wk. Benzbromarone (BBR, 10mg/kg/day, diet, from weeks 0 to 5), a URATv1 transporter inhibitor, was administered in the SU/Hx/Nx-rats with or without 2%OA. To examine the role of XOR in PAH, XOR+/− and wild type (WT) mice were exposed to 3-wk Nx or Hx (10% O2). Results The mRNA of URATv1 was detected in the normal lungs. Isometric tension study showed that UA (8 mg/dl) inhibited acetylcholine-induced vasorelaxation. In perfused lung preparations, UA acutely increased estimated PVR in a dose-dependent manner (1.6–16.0mg/dl) with reducing cGMP levels in the lungs. BBR significantly attenuated the pressor response to UA. UA levels in the plasma and the lung tissues were significantly elevated in SU/Hx/Nx-rats with 2%OA (normal vs. vehicle vs. 2%OA, plasma: 0.24±0.01 vs. 0.80±0.14 and 1.44±0.17 mg/dl; lung tissues: 68±3 vs. 142±3 and 377±46 pmol/g tissue). They exhibited further elevation of right ventricle systolic pressure (RVSP) (31±2 vs. 72±6 vs. 101±3 mmHg) and Ea (a marker of RV afterload) (0.24±0.04 vs. 0.97±0.15 vs. 2.36±0.49 mmHg/μL) with the exacerbation of occlusive lesions of PAs. BBR had no changes in the UA levels in the plasma (1.93±0.30 mg/dL), but significantly reduced the UA levels in the lung tissues (101±10 pmol/g tissue) and attenuated the increase in RVSP (53±8mmHg) and Ea (0.21±0.05 mmHg/mL) in the SU/Hx/Nx-rats with 2%OA. On the other hand, BBR had no effects on RVSP (76±7 mmHg) and Ea (0.91±0.15 mmHg/mL) in the SU/Hx/Nx-rats without 2%OA. There were no significant differences in RVSP between XOR+/− mice with Hx and WT with Hx (26±2 vs. 26±2 mmHg). Conclusions Hyperuricemia itself impairs endothelial function and deteriorates PAH via URATv1 in a XOR-independent manner. UA can be a novel therapeutic target for PAH. Funding Acknowledgement Type of funding source: None