Abstract 542: The Effects of Soluble Epoxide Hydrolase Inhibition in Atherogenesis and Atherosclerotic Progression

Abstract

Epoxyeicosatrienoic acids (EETs), metabolites of arachidonic acid (AA), are known to have anti-inflammatory effects and hydrolyzed by soluble epoxide hydrolase (sEH). We aimed to investigate the effect of sEH inhibition on atherosclerotic progression. LDLR-/- mice with or without sEH inhibitor and LDLR and sEH double knockout (DK) mice were fed with western diet for 6 weeks to induce arteriosclerosis, and then half of the mice switched to chow diet supplemented with sEH inhibitor for another 6 weeks. To further assess the role of sEH in atherosgenesis, we transplanted LDLR-/- or DK bone marrow into LDLR-/- recipients and also fed with 6 weeks western diet. The progression of atherosclerosis was evaluated and AA metabolites were analyzed by LC-MS/MS. The results revealed that sEH inhibition and gene knockout decreased western diet-induced high plasma LDL cholesterol level and the size of the atherosclerotic lesion in the aorta of the mice. Furthermore, mice with DK bone marrow transplantation developed less aortic lesion by less ly6chi monocyte infiltiation without diminished the cholesterol level in plasma. After diet switch, the cholesterol level dropped back to control level and the size of arotic lesion became smaller compared to the western diet group. When sEH inhibitor decreased sEH activity in the liver and increased EETs/DHETs ratio in the plasma, the plaque size seemed not being further reduced after diet switch. However, M2 type macrophage marker at protein and mRNA level was increased in the aortic lesions. In cultured macrophage, sEH inhibition and EETs supplements could increase the markers of M2 macrophage at mRNA level. Thus, sEH inhibition and depletion in macrophage attenuated atherosclerosis when fed with western diet. Although the role of the sEH inhibitor on atherosclerosis progression and plaque stability need to be further investigated. EETs levels and sEH activity may play a pivotal role in atherogenesis and monocyte/macrophage in filtration and differentiation.