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Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension
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 progre...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075373/ https://www.ncbi.nlm.nih.gov/pubmed/34845934 http://dx.doi.org/10.1161/JAHA.121.022712 |
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author | Watanabe, Takanori Ishikawa, Mariko Abe, Kohtaro Ishikawa, Tomohito Imakiire, Satomi Masaki, Kohei Hosokawa, Kazuya Fukuuchi, Tomoko Kaneko, Kiyoko Ohtsubo, Toshio Hirano, Mayumi Hirano, Katsuya Tsutsui, Hiroyuki |
author_facet | Watanabe, Takanori Ishikawa, Mariko Abe, Kohtaro Ishikawa, Tomohito Imakiire, Satomi Masaki, Kohei Hosokawa, Kazuya Fukuuchi, Tomoko Kaneko, Kiyoko Ohtsubo, Toshio Hirano, Mayumi Hirano, Katsuya Tsutsui, Hiroyuki |
author_sort | Watanabe, Takanori |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9075373 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-90753732022-05-10 Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension Watanabe, Takanori Ishikawa, Mariko Abe, Kohtaro Ishikawa, Tomohito Imakiire, Satomi Masaki, Kohei Hosokawa, Kazuya Fukuuchi, Tomoko Kaneko, Kiyoko Ohtsubo, Toshio Hirano, Mayumi Hirano, Katsuya Tsutsui, Hiroyuki J Am Heart Assoc Original Research 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. John Wiley and Sons Inc. 2021-11-30 /pmc/articles/PMC9075373/ /pubmed/34845934 http://dx.doi.org/10.1161/JAHA.121.022712 Text en © 2021 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ (https://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. |
spellingShingle | Original Research Watanabe, Takanori Ishikawa, Mariko Abe, Kohtaro Ishikawa, Tomohito Imakiire, Satomi Masaki, Kohei Hosokawa, Kazuya Fukuuchi, Tomoko Kaneko, Kiyoko Ohtsubo, Toshio Hirano, Mayumi Hirano, Katsuya Tsutsui, Hiroyuki Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title | Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title_full | Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title_fullStr | Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title_full_unstemmed | Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title_short | Increased Lung Uric Acid Deteriorates Pulmonary Arterial Hypertension |
title_sort | increased lung uric acid deteriorates pulmonary arterial hypertension |
topic | Original Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9075373/ https://www.ncbi.nlm.nih.gov/pubmed/34845934 http://dx.doi.org/10.1161/JAHA.121.022712 |
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