Wang_2015_Am.J.Physiol.Heart.Circ.Physiol__ajpheart 00289 2015

Epoxyeicosatrienoic acids (EETs) have beneficial effects on cardiovascular disease. Soluble epoxide hydrolase (sEH) metabolizes EETs to less active diols, thus diminishing 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 VSMC 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 post-transcriptionally and promoted cell proliferation and migration, the latter effect could be largely attenuated by sEH inhibitor. Adenovirus-mediated overexpression of sEH could mimic the effect of PDGF-BB, induced VSMC proliferation and migration. In vivo, sEH inhibitor significantly decreased the injury-induced neointima formation in a rat carotid-artery injury model. These data establish the impact of sEH expression on atherosclerotic progression and vascular remodeling after injury, thus identifying a novel integrative role of sEH in VSMC phenotypic modulation and migration. Blocking sEH activity may be a potential therapeutic approach for ameliorating vascular occlusive disease.