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Differential Effects of sEH Inhibitors on Vascular Smooth Muscle Cell Proliferation and Migration
Author(s) -
Kim Hyo Seon,
Kang Keon Wook
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.lb539
Subject(s) - vascular smooth muscle , epoxyeicosatrienoic acid , epoxide hydrolase 2 , chemistry , downregulation and upregulation , neointima , cell growth , platelet derived growth factor receptor , pharmacology , arachidonic acid , biochemistry , microbiology and biotechnology , medicine , endocrinology , biology , growth factor , enzyme , restenosis , receptor , smooth muscle , stent , gene
Epoxyeicosatrienoic acid (EET), an arachidonic acid metabolite, is known to have anti‐inflammatory and cardioprotective effects. EET is metabolized by soluble epoxide hydrolase (sEH) into dihydroxyeicosatrienoic acid (DHET). Neointimal hyperplasia results from atypical proliferation and migration of vascular smooth muscle cells (VSMCs), which leads to vascular diseases including atherosclerosis and restenosis. Our study aim is to assess the potential role of sEH inhibitors on proliferation and migration of VSMCs. sEH inhibitor AUDA (12‐[[(tricyclo[3.3.1.13,7]dec‐1‐ylamino)carbonyl]amino]‐dodecanoic acid) and CDU (NCND, N‐Cyclohexyl‐N′‐dodecylurea) inhibited platelet‐derived growth factor (PDGF)‐induced proliferation of rat VSMCs. Nrf2 activation and subsequent heme‐oxygenase‐1 (HO‐1) induction are reported to attenuate neointima formation. AUDA decreased Keap1 expression while increasing Nrf2 nuclear translocation in VSMCs. Also, in higher concentrations (above 10 μg/mL) AUDA induced HO‐1 expression. Our lab previously reported peptidyl/prolyl isomerase Pin1 upregulation in neointima lesions of the femoral artery. Pin1 overexpression inhibited HO‐1 expression as well as Nrf2/anti‐oxidant response element (ARE) pathway in VSMCs. In accordance with it, AUDA concentration‐dependently inhibited PDGF‐induced Pin1 expression. However, exogenous EET had little effect on HO‐1 and Pin1 expression or VSMC proliferation. Thus, sEH inhibitors regulate VSMC proliferation by HO‐1 induction and Pin1 suppression, which is possibly irrelevant to EET stabilization. On the other hand, AUDA increased PDGF‐induced migration of VSMCs. Cyclooxygenase‐2 (COX‐2) metabolizes arachidonic acid to thromboxanes and prostaglandins, some of which are known to promote VSMC migration. sEH inhibitors AUDA and CDU increased PDGF‐induced COX‐2 expression in a concentration‐dependent manner. Further, AUDA increased PDGF‐induced prostaglandin E2 (PGE 2 ) secretion, which was attenuated by co‐treatment with COX‐2 selective inhibitor celecoxib. Also, celecoxib significantly inhibited the enhancement of PDGF‐induced VSMC migration by AUDA. However, celecoxib did not alter the effect of AUDA on PDGF‐induced proliferation, indicating COX‐2 specifically induces VSMC migration. When treated with AUDA, PGE 2 receptor EP antagonists AH6809 and L‐161,982 did not affect PDGF‐induced VSMC migration, while thromboxane A2 (TXA 2 ) receptor TP antagonist ICI192,605 and PGI 2 receptor IP antagonist CAY10441 significantly suppressed it. However, CAY10441 reduced PDGF‐induced VSMC migration even without AUDA, implying its effect might be nonspecific. Therefore, enhanced PDGF‐induced migration by AUDA may be attributable to COX‐2‐meidated TXA 2 formation. In conclusion, sEH inhibitors have differential effects on PDGF‐induced VSMC proliferation and migration; inhibition of PDGF‐induced VSMC proliferation via Pin1 inhibition and potentiation of PDGF‐induced VSMC migration via COX‐2 induction and subsequent TXA 2 production.