Increased lung uric acid deteriorates pulmonary arterial hypertension

Takanori Watanabe, Mariko Ishikawa, Kohtaro Abe, Tomohito Ishikawa, Satomi Imakiire, Kohei Masaki, Kazuya Hosokawa, Tomoko Fukuuchi, Kiyoko Kaneko, Toshio Ohtsubo, Mayumi Hirano, Katsuya Hirano, Hiroyuki Tsutsui

研究成果: ジャーナルへの寄稿学術誌査読

8 被引用数 (Scopus)

抄録

BACKGROUND: Recent 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 RESULTS: In 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 benzbromar-one, a UA transporter inhibitor, or L-norvaline, an arginase inhibitor. In PAH model rats, induction of hyperuricemia by adminis-tering 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 (xan-thine 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. CONCLUSIONS: Increased 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.

本文言語英語
論文番号e022712
ジャーナルJournal of the American Heart Association
10
23
DOI
出版ステータス出版済み - 12月 7 2021

!!!All Science Journal Classification (ASJC) codes

  • 循環器および心血管医学

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