title: Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration.
abstract: Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing their biological activity. sEH inhibitors can suppress the progression of atherosclerotic lesions in animal models. However, the regulation of sEH in vascular smooth muscle cells (VSMCs) and role of sEH in patients with atherosclerosis have not been evaluated. We hypothesize that sEH in VSMCs plays a pivotal role in atherosclerosis and injury-induced neointima formation. In this study, sEH expression in human autopsy atherosclerotic plaque was determined by immunohistochemistry. In cultured rat and human VSMCs, the phenotypic switching marker and sEH expression induced by platelet-derived growth factor-BB (PDGF-BB) were examined by Western blot analysis. Carotid-artery balloon injury was performed after adenovirus-mediated overexpression of sEH or oral administration of a potent sEH inhibitor in Sprague-Dawley rats. sEH was highly expressed in VSMCs of the intima and media within human atherosclerotic plaque. In vitro, PDGF-BB upregulated the expression in VSMCs after transcription and promoted cell proliferation and migration; the latter effect could be largely attenuated by an sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB and induce VSMC proliferation and migration. In vivo, the sEH inhibitor led to a significant decrease in injury-induced neointima formation in a rat carotid-artery injury model. These data establish the effect of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role for sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China; Department of Physiology and Pathophysiology, Shanghai Medical College, Fudan University, Shanghai, China;
authors.forename: Qingjie
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China;
authors.forename: Leijun
authors.initials: L
authors.lastname: Huo
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China;
authors.forename: Jinlong
authors.initials: J
authors.lastname: He
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China;
authors.forename: Wenshuang
authors.initials: W
authors.lastname: Ding
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China;
authors.forename: Hang
authors.initials: H
authors.lastname: Su
authors.affiliation: Department of Pathology, Shantou University Medical College, Shantou, Guangdong, China;
authors.forename: Dongping
authors.initials: D
authors.lastname: Tian
authors.affiliation: Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York; and.
authors.forename: Carrie
authors.initials: C
authors.lastname: Welch
authors.affiliation: Department of Entomology and Comprehensive Cancer Center, University of California, Davis, California.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China;
authors.forename: Ding
authors.initials: D
authors.lastname: Ai
authors.affiliation: Department of Physiology and Pathophysiology, Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Medical University, Tianjin, China; zhuyi@tmu.edu.cn.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D050197:Atherosclerosis / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D000077214:Becaplermin; D020212:Carotid Artery Injuries / Q000201:enzymology* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D054337:Cell Dedifferentiation; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002478:Cells, Cultured; D003324:Coronary Artery Disease / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D058426:Neointima; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D066253:Vascular Remodeling; D055815:Young Adult
chemical_list: C561619:1-(1-methanesulfonylpiperidin-4-yl)-3-(4-trifluoromethoxyphenyl)urea; D015777:Eicosanoids; D004791:Enzyme Inhibitors; D010671:Phenylurea Compounds; D010880:Piperidines; D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D004851:Epoxide Hydrolases; C506428:EPHX2 protein, human; C518648:Ephx2 protein, mouse
keywords: atherosclerosis; migration; neointima formation; soluble epoxide hydrolase inhibitor; vascular smooth muscle cell