Eicosapentaenoic acid ameliorates pulmonary hypertension via inhibition of tyrosine kinase Fyn. (November 2020)

• Record Type: Journal Article
• Authors: Kurahara, Lin Hai; Hiraishi, Keizo; Yamamura, Aya; Zhang, Ying; Abe, Kohtaro; Yahiro, Eiji; Aoki, Mikiko; Koga, Kaori; Yokomise, Hiroyasu; Go, Tetsuhiko; Ishikawa, Kaori; Bo, Zhang; Kishi, Hiroko; Kobayashi, Sei; Aoki-Shoi, Narumi; Toru, Satoh; Inoue, Ryuji; Hirano, Katsuya
• Is Part Of: Journal of molecular and cellular cardiology. Volume 148(2020)
• Page Start: 50
• Page End: 62
• Publication Date: 2020-11
• Subjects: 5-HT 5-hydroxytryptamine -- α-SMA α-smooth muscle actin -- EndoMT Endothelial-mesenchymal transition -- EPA Eicosapentaenoic acid -- HR Heart rate -- HPAECs Human pulmonary artery endothelial cells -- HPASMCs Human pulmonary artery smooth muscle cells -- IPAH Idiopathic pulmonary arterial hypertension -- IL-6 Interleukin-6 -- KM-FYN Dominant negative Fyn -- MCT Monocrotaline -- PAs Pulmonary arteries -- PAAT Pulmonary artery acceleration time -- PAH Pulmonary arterial hypertension -- p-STAT3 phosphorylated STAT3 -- RvE1 Resolvin E1 -- RVID Right ventricular internal diameter -- RVWT Right ventricular wall thickness -- STAT3 Signal transducer and activator of transcription 3 -- TGF-β2 Transforming growth factor-β2 -- VE-cadherin Vascular endothelial cadherin -- FY-FYN Constitutively active Fyn; Eicosapentaenoic acid -- Pulmonary arterial hypertension -- Src family tyrosine kinases -- Human pulmonary artery endothelial cells -- Endothelial-to-mesenchymal transition -- Human pulmonary artery smooth muscle cells; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2020.08.013
• Languages: English
• ISSNs: 0022-2828

Abstract

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. Graphical abstract: Unlabelled Image Highlights: Administration of EPA ameliorated cardiovascular remodeling in PAH rats. EPA and RvE1 suppressed vasocontraction in rats and human PA. Fyn activity is a key regulator of STAT3 phosphorylation in HPAECs and HPASMCs. EPA and RvE1 downregulate SRC family activity in HPAECs and HPASMCs. EPA and RvE1 suppressed proliferation of IPAH-PASMCs.