Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration

Abstract

. Soluble epoxide hydrolase is involved in the development of atherosclerosis and arterial neointima formation by regulating smooth muscle cell migration. Am J Physiol Heart Circ Physiol 309: H1894 -H1903, 2015. First published October 9, 2015; doi:10.1152/ajpheart.00289.2015.-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 plateletderived 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.

Inhibition of polycomb repressor complex 2 ameliorates neointimal hyperplasia by suppressing trimethylation of H3K27 in vascular smooth muscle cells

“…All rats were housed in a temperature‐controlled environment in cages containing with wood shavings as bedding (two to three per cage) with 12‐hr light/dark cycles and received food and water ad libitum. Carotid wire‐guided injury was used to model restenosis (Wang et al, ). Briefly, 0.1% heparin sodium was injected via the tail vein of rats at 0.1 mg.100 .…”

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

“…EETs are produced by the metabolism of arachidonic acid (substrate) through CYP-epoxygenases, which are known to play an important role in protection against ischemic injury, and act as vasodilators in arteries from the brain, intestines, skeletal muscle, heart, and aorta [4-10]. In arteries, sEH is highly expressed in endothelial cells and present lesser in smooth muscle cells [7,11,12]. Genetic deletion and inhibition of sEH protected against myocardial ischemia-reperfusion injury, improved vascular function, and decreased blood pressure in various disease models [13-16].…”

Atheroprotective Effects and Molecular Targets of Tanshinones Derived From Herbal Medicine Danshen

“…132 sEH inhibitors have been shown to attenuate lesion development in hyperlipidemic LDLr −/−133 or ApoE −/− mice. 134 Mechanistic studies showed that sEH inhibitors attenuated the proliferation of SMCs 135,136 and promoted reverse cholesterol transport. 133 A more recent study 137 has shown that TSN functions as a sEH inhibitor (IC 50 = 1.36 μM) by blocking the conversion of 8, 9-EET to 8, 9-DHET catalyzed by sEH in vitro.…”