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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1265.)
© 2009 American Heart Association, Inc.

National Cholesterol Awareness Month

Inhibition of Soluble Epoxide Hydrolase Attenuated Atherosclerosis, Abdominal Aortic Aneurysm Formation, and Dyslipidemia

Le-Ning Zhang; Jon Vincelette; Ying Cheng; Upasana Mehra; Dawn Chen; Sampath-Kumar Anandan; Richard Gless; Heather K. Webb; Yi-Xin (Jim) Wang

From Arête Therapeutics Inc, Hayward, Calif.

Correspondence to Le-Ning Zhang, Arête Therapeutics Inc, 3912 Trust Way, Hayward, CA 94545. E-mail lzhang{at}aretetherapeutics.com

Abstract

Objective— Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects.

Methods and Results— Six-month-old apolipoprotein E–deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall.

Conclusions— The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.

In Ang II–infused apoE KO mice, the s-EH inhibitor AR9276 attenuated aneurysm formation and atherosclerosis development. These effects are associated with reduction of inflammatory cell infiltration in the vascular wall and downregulation of the expression of proinflammatory mediators in the vasculature and blood, as well as correction of dyslipidemia.

Key Words: epoxyeicosatrienoic acids • soluble epoxide hydrolase • dyslipidemia • atherosclerosis • abdominal aorta aneurysm • inflammatory markers