Abstract
Epoxyeicosatrienoic acid (EET) is a cardioprotective metabolite of arachidonic acid. It is known that soluble epoxide hydrolase (sEH) is involved in the metabolic degradation of EET. The abnormal proliferation and migration of vascular smooth muscle cells (VSMCs) play important roles in the pathogenesis of atherosclerosis and restenosis. Thus, the present study investigated the effects of the sEH inhibitor 12-(((tricyclo(3.3.1.13,7)dec-1-ylamino)carbonyl)amino)-dodecanoic acid (AUDA) on platelet-derived growth factor (PDGF)-induced proliferation and migration in rat VSMCs. AUDA significantly inhibited PDGF-induced rat VSMC proliferation, which coincided with Pin1 suppression and heme oxygenase-1 (HO-1) upregulation. However, exogenous 8,9-EET, 11,12-EET, and 14,15-EET treatments did not alter Pin1 or HO-1 levels and had little effect on the proliferation of rat VSMCs. On the other hand, AUDA enhanced the PDGF-stimulated cell migration of rat VSMCs. Furthermore, AUDA-induced activation of cyclooxygenase-2 (COX-2) and subsequent thromboxane A2 (TXA2) production were required for the enhanced migration. Additionally, EETs increased COX-2 expression but inhibited the migration of rat VSMCs. In conclusion, the present study showed that AUDA exerted differential effects on the proliferation and migration of PDGF-stimulated rat VSMCs and that these results may not depend on EET stabilization.
Highlights
Coronary heart disease is a leading cause of death in developed countries and accounts for one in seven deaths in the United States [1]
Effects of AUDA on vascular smooth muscle cells (VSMCs) Proliferation. It was assessed whether the soluble epoxide hydrolase (sEH) inhibitors AUDA and cyclohexyl-3-dodecyl urea (CDU) inhibit the platelet-derived growth factor (PDGF)-induced proliferation of rat VSMCs
Both AUDA and CDU dose-dependently suppressed the proliferation of rat VSMCs exposed to PDGF for 48 h (Figures 1A,B and S1)
Summary
Coronary heart disease is a leading cause of death in developed countries and accounts for one in seven deaths in the United States [1]. PDGF enhances the migration and proliferation of vascular smooth muscle cells (VSMCs) and fibroblasts in the media and adventitia of the vasculature, which subsequently contributes to the formation of neointima and reduces the size of the lumen [4,5,6]. EET is hydrolyzed by soluble epoxide hydrolase (sEH) into dihydroxyeicosatrienoic acid (DHET), which is active but readily degraded [10]. It is well-documented that EET exerts cardioprotective effects by preventing hypertension and reducing inflammation [11,12,13,14]. It was demonstrated that AUDA induced the activation of cyclooxygenase-2 (COX-2) in PDGF-treated VSMCs, suggesting that surplus thromboxane A2 (TXA2) production might be related to enhanced VSMC migration
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