Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation and dyslipidemia in apolipoprotein E deficient mice infused with angiotensin II

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Objective‐Epoxyeicosatrienoic acids (EETs) have been shown to have anti‐inflammatory effects. So they 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 is 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/day) 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 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 IL‐6, murine IL‐8 KC and IL‐1α, and down‐regulation of gene expressions of ICAM‐1, VCAM‐1 and IL‐6 in the arterial wall. AR9276 treatment also lowered LDL and elevated HDL levels. Conclusions‐The present data demonstrate that treatment with an s‐EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant down‐regulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.

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