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

Hidenori Moriyama, Jin Endo (), Masaharu Kataoka, Yuta Shimanaka, Nozomu Kono, Yuki Sugiura, Shinichi Goto, Hiroki Kitakata, Takahiro Hiraide, Naohiro Yoshida, Sarasa Isobe, Tsunehisa Yamamoto, Kohsuke Shirakawa, Atsushi Anzai, Yoshinori Katsumata, Makoto Suematsu, Kenjiro Kosaki, Keiichi Fukuda, Hiroyuki Arai and Motoaki Sano
Additional contact information
Hidenori Moriyama: Keio University School of Medicine
Jin Endo: Keio University School of Medicine
Masaharu Kataoka: Keio University School of Medicine
Yuta Shimanaka: University of Tokyo
Nozomu Kono: University of Tokyo
Yuki Sugiura: Keio University School of Medicine
Shinichi Goto: Keio University School of Medicine
Hiroki Kitakata: Keio University School of Medicine
Takahiro Hiraide: Keio University School of Medicine
Naohiro Yoshida: Keio University School of Medicine
Sarasa Isobe: Keio University School of Medicine
Tsunehisa Yamamoto: Keio University School of Medicine
Kohsuke Shirakawa: Keio University School of Medicine
Atsushi Anzai: Keio University School of Medicine
Yoshinori Katsumata: Keio University School of Medicine
Makoto Suematsu: Keio University School of Medicine
Kenjiro Kosaki: Keio University School of Medicine
Keiichi Fukuda: Keio University School of Medicine
Hiroyuki Arai: University of Tokyo
Motoaki Sano: Keio University School of Medicine

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-30621-z

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