Tyrosine Kinase FYN Inhibition Mediates the Therapeutic Effects of Eicosapentaenoic Acid on Pulmonary Hypertension

Background and Purpose: Pulmonary arterial hypertension (PAH) is a multifactorial disease characterized by pulmonary arterial remodeling in which the Src family non-receptor tyrosine kinases including Fyn play non-trivial roles. In this study, we explored the therapeutic potential of eicosapentaenoic acid (EPA) and its metabolite resolvin E1 (RvE1) for PAH through inhibition of Fyn in vitroand in vivo. Method: Cardiodynamic parameters of rat hearts were measured by the echocardiography. Contractile responses of isolated pulmonary arteries were examined by the isometric tension measurement. Proliferation of human pulmonary artery smooth muscle cells (HPASMCs) derived from PAH patients were evaluated by the MTT assay. Stress fiber formation and STAT3 phosphorylation in HPAECs and HPASMCs were examined by immunohistochemical and western blot analyses, respectively. Results : Administration of EPA to MCT-treated rats significantly improved the pathological changes characteristic for PAH, i.e. pulmonary arterial thickening, right ventricle dysfunction and cardiovascular fibrosis. Pulmonary arteries from MCT-treated rats showed exaggerated contractile responses compared with those from vehicle-treated rats, which were greatly normalized by EPA treatment. Administration of EPA or RvE1 decelerated the enhanced proliferation of PAH patient-derived PASMCs. Immunocytochemical and western blot analyses showed that a dominant negative form of Fyn prevented TGF-β2-induced stress fiber formation and IL-6-induced STAT3 phosphorylation. EPA and RvE1 suppressed Src family activity by modulating it's autophosphorylation level. Summary: EPA significantly improved PAH-associated pathophysiology and cardiac dysfunction, which is likely mediated at least in part via Fyn inhibition. These results also point to the therapeutic significance of targeting this molecule in PAH treatment. Symposium