Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn

Lin Hai Kurahara, Keizo Hiraishi, Aya Yamamura, Ying Zhang, Kohtaro Abe, Eiji Yahiro, Mikiko Aoki, Kaori Koga, Hiroyasu Yokomise, Tetsuhiko Go, Kaori Ishikawa, Zhang Bo, Hiroko Kishi, Sei Kobayashi, Narumi Aoki-Shoi, Satoh Toru, Ryuji Inoue, Katsuya Hirano

Research output: Contribution to journalArticlepeer-review

Abstract

Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial vasoconstriction and remodeling. Src family tyrosine kinases, including Fyn, play critical roles in vascular remodeling via the inhibition of STAT3 signaling. EPA is known to inhibit Fyn kinase activity. This study investigated the therapeutic potential and underlying mechanisms of EPA and its metabolite, resolvin E1 (RvE1), to treat PAH using monocrotaline-induced PAH model rats (MCT-PAH), human pulmonary artery endothelial cells (HPAECs), and human pulmonary artery smooth muscle cells (HPASMCs). Administration of EPA 1 and 2 weeks after MCT injection both ameliorated right ventricular hypertrophy, remodeling and dysfunction, and medial wall thickening of the pulmonary arteries and prolonged survival in MCT-PAH rats. EPA attenuated the enhanced contractile response to 5-hydroxytryptamine in isolated pulmonary arteries of MCT-PAH rats. Mechanistically, the treatment with EPA and RvE1 or the introduction of dominant-negative Fyn prevented TGF-β2-induced endothelial-to-mesenchymal transition and IL-6-induced phosphorylation of STAT3 in cultured HPAECs. EPA and RvE1 suppressed Src family kinases' activity as evaluated by their phosphorylation status in cultured HPAECs and HPASMCs. EPA and RvE1 suppressed vasocontraction of rat and human PA. Furthermore, EPA and RvE1 inhibited the enhanced proliferation and activity of Src family kinases in HPASMCs derived from patients with idiopathic PAH. EPA ameliorated PAH's pathophysiology by mitigating vascular remodeling and vasoconstriction, probably inhibiting Src family kinases, especially Fyn. Thus, EPA is considered a potent therapeutic agent for the treatment of PAH.

Original languageEnglish
Pages (from-to)50-62
Number of pages13
JournalJournal of Molecular and Cellular Cardiology
Volume148
DOIs
Publication statusPublished - Nov 2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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