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Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling

Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells mig...

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Autores principales: Moriyama, Hidenori, Endo, Jin, Kataoka, Masaharu, Shimanaka, Yuta, Kono, Nozomu, Sugiura, Yuki, Goto, Shinichi, Kitakata, Hiroki, Hiraide, Takahiro, Yoshida, Naohiro, Isobe, Sarasa, Yamamoto, Tsunehisa, Shirakawa, Kohsuke, Anzai, Atsushi, Katsumata, Yoshinori, Suematsu, Makoto, Kosaki, Kenjiro, Fukuda, Keiichi, Arai, Hiroyuki, Sano, Motoaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156667/
https://www.ncbi.nlm.nih.gov/pubmed/35641514
http://dx.doi.org/10.1038/s41467-022-30621-z
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author Moriyama, Hidenori
Endo, Jin
Kataoka, Masaharu
Shimanaka, Yuta
Kono, Nozomu
Sugiura, Yuki
Goto, Shinichi
Kitakata, Hiroki
Hiraide, Takahiro
Yoshida, Naohiro
Isobe, Sarasa
Yamamoto, Tsunehisa
Shirakawa, Kohsuke
Anzai, Atsushi
Katsumata, Yoshinori
Suematsu, Makoto
Kosaki, Kenjiro
Fukuda, Keiichi
Arai, Hiroyuki
Sano, Motoaki
author_facet Moriyama, Hidenori
Endo, Jin
Kataoka, Masaharu
Shimanaka, Yuta
Kono, Nozomu
Sugiura, Yuki
Goto, Shinichi
Kitakata, Hiroki
Hiraide, Takahiro
Yoshida, Naohiro
Isobe, Sarasa
Yamamoto, Tsunehisa
Shirakawa, Kohsuke
Anzai, Atsushi
Katsumata, Yoshinori
Suematsu, Makoto
Kosaki, Kenjiro
Fukuda, Keiichi
Arai, Hiroyuki
Sano, Motoaki
author_sort Moriyama, Hidenori
collection PubMed
description Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-β signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension.
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spelling pubmed-91566672022-06-02 Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling Moriyama, Hidenori Endo, Jin Kataoka, Masaharu Shimanaka, Yuta Kono, Nozomu Sugiura, Yuki Goto, Shinichi Kitakata, Hiroki Hiraide, Takahiro Yoshida, Naohiro Isobe, Sarasa Yamamoto, Tsunehisa Shirakawa, Kohsuke Anzai, Atsushi Katsumata, Yoshinori Suematsu, Makoto Kosaki, Kenjiro Fukuda, Keiichi Arai, Hiroyuki Sano, Motoaki Nat Commun Article Pulmonary hypertension is a fatal rare disease that causes right heart failure by elevated pulmonary arterial resistance. There is an unmet medical need for the development of therapeutics focusing on the pulmonary vascular remodeling. Bioactive lipids produced by perivascular inflammatory cells might modulate the vascular remodeling. Here, we show that ω-3 fatty acid-derived epoxides (ω-3 epoxides) released from mast cells by PAF-AH2, an oxidized phospholipid-selective phospholipase A2, negatively regulate pulmonary hypertension. Genetic deletion of Pafah2 in mice accelerate vascular remodeling, resulting in exacerbation of hypoxic pulmonary hypertension. Treatment with ω-3 epoxides suppresses the lung fibroblast activation by inhibiting TGF-β signaling. In vivo ω-3 epoxides supplementation attenuates the progression of pulmonary hypertension in several animal models. Furthermore, whole-exome sequencing for patients with pulmonary arterial hypertension identifies two candidate pathogenic variants of Pafah2. Our findings support that the PAF-AH2-ω-3 epoxide production axis could be a promising therapeutic target for pulmonary hypertension. Nature Publishing Group UK 2022-05-31 /pmc/articles/PMC9156667/ /pubmed/35641514 http://dx.doi.org/10.1038/s41467-022-30621-z Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Moriyama, Hidenori
Endo, Jin
Kataoka, Masaharu
Shimanaka, Yuta
Kono, Nozomu
Sugiura, Yuki
Goto, Shinichi
Kitakata, Hiroki
Hiraide, Takahiro
Yoshida, Naohiro
Isobe, Sarasa
Yamamoto, Tsunehisa
Shirakawa, Kohsuke
Anzai, Atsushi
Katsumata, Yoshinori
Suematsu, Makoto
Kosaki, Kenjiro
Fukuda, Keiichi
Arai, Hiroyuki
Sano, Motoaki
Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title_full Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title_fullStr Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title_full_unstemmed Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title_short Omega-3 fatty acid epoxides produced by PAF-AH2 in mast cells regulate pulmonary vascular remodeling
title_sort omega-3 fatty acid epoxides produced by paf-ah2 in mast cells regulate pulmonary vascular remodeling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9156667/
https://www.ncbi.nlm.nih.gov/pubmed/35641514
http://dx.doi.org/10.1038/s41467-022-30621-z
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