1. Academic Validation
  2. Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension

  • J Am Heart Assoc. 2021 Dec 7;10(23):e022712. doi: 10.1161/JAHA.121.022712.
Takanori Watanabe 1 2 Mariko Ishikawa 1 2 3 Kohtaro Abe 1 Tomohito Ishikawa 1 2 Satomi Imakiire 1 2 Kohei Masaki 1 2 Kazuya Hosokawa 1 Tomoko Fukuuchi 4 Kiyoko Kaneko 4 Toshio Ohtsubo 5 Mayumi Hirano 6 7 Katsuya Hirano 7 Hiroyuki Tsutsui 1 2
Affiliations

Affiliations

  • 1 Department of Cardiovascular Medicine Kyushu University Graduate School of Medical Sciences Fukuoka Japan.
  • 2 Division of Cardiovascular Medicine Research Institute of Angiocardiology Graduate School of Medical Sciences Kyushu University Fukuoka Japan.
  • 3 Department of Anesthesiology and Critical Care Medicine Kyushu University Graduate School of Medical Sciences Fukuoka Japan.
  • 4 Faculty of Pharma-Science Teikyo University Tokyo Japan.
  • 5 Department of Internal Medicine Japanese Red Cross Fukuoka Hospital Fukuoka Japan.
  • 6 Division of Molecular Cardiology Research Institute of Angiocardiology Graduate School of Medical Sciences Kyushu University Fukuoka Japan.
  • 7 Department of Cardiovascular Physiology Faculty of Medicine Kagawa University Miki-cho, Kita-gun Kagawa Japan.
Abstract

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 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. 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.

Keywords

URATv1; arginase; pulmonary arterial hypertension; uric acid; xanthine oxidoreductase.

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