Differential Effects of sEH Inhibitors on the Proliferation and Migration of Vascular Smooth Muscle Cells

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.

Deletion of soluble epoxide hydrolase suppressed chronic kidney disease-related vascular calcification by restoring Sirtuin 3 expression

“…However, since only using chemical inhibitor without specific knockdown of sEH, it could not fully rule out the effects of the complete sEH protein on the process of vascular calcification. In fact, several studies have reported that the effect of sEH inhibitors could be different from genetic knockout of sEH [ 16 ]. For example, despite many studies that had shown that genetic deletion of sEH decreased the pathogenicity of several diseases, both Li et al [ 17 ] and Hutchens et al [ 18 ] reported that deficiency of sEH in mice exacerbates cardiac dysfunction.…”

Multitarget molecule, PTUPB, to treat diabetic nephropathy in rats

“…Inhibition of a specific biosynthetic arachidonic acid pathway could alter the metabolic flux resulting in side effects (Sonnweber et al, 2018). Interactions and changes in metabolic flux have been determined for COX-2 and sEH inhibitors (Kim et al, 2017). PTUPB is a dual acting molecule and that concurrently inhibits sEH and COX-2 resulting in potent kidney protective effects while reducing side effects (Hye Khan et al, 2016;Wang et al, 2018).…”

Prospective for cytochrome P450 epoxygenase cardiovascular and renal therapeutics

“…Vascular beneficial therapeutic actions for sEH inhibitors extends to atherosclerosis and vascular remodeling (Fleming, 2001; Imig, 2012; Imig & Hammock, 2009). Vascular smooth muscle cell culture experiments have ascertained that sEH inhibitors decrease proliferation and migration (Davis et al, 2002; Fleming, 2001; Kim et al, 2017). Acute vascular inflammation in mice is attenuated by increased endothelial cell EET levels or sEH inhibition (Deng et al, 2011).…”