Abstract 9460: Inhibition of Soluble Epoxide Hydrolase (sEH) Reduces Atherogenesis in Mice
Background: Epoxyeicosatrienoic acids (EETs) are short-living, endothelium-derived factors efficiently promoting vasodilatation and angiogenesis. Recently, EETs have been identified as potent anti-inflammatory agents and stimulators of lipid metabolism. Physiologically, EETs are rapidly converted into dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase (sEH). Thus, inhibition of sEH revealed potent anti-inflammatory properties. Here, we test the hypothesis that inhibition of soluble epoxide hydrolase by the orally available compound BIX01753 modulates atherogenesis in vivo.
Methods and Results: A prevention arm was designed to test for the potency to inhibit de novo atherosclerosis. LDLR-deficient mice either received a high cholesterol diet, a high cholesterol diet supplemented with two doses of BIX01753, or a low cholesterol diet for 16 weeks. When fed the high cholesterol diet and the higher dose of the sEH-inhibitor, mice showed significantly lower lipid depositions in the abdominal aorta as compared to the control (39±2% vs. 29±2% Oil-Red-O positive area, n=17, p=0.03), but not with the lower dose. Intimal lesion size in sections of the aortic arches, generally considered as an indicator of late atherosclerotic lesions, decreased up to 29±4% (n=15, p<0.01), whereas the size of older lesions in aortic roots was not altered significantly. Interestingly, mice fed the sEH-inhibitor showed no changes for the content of smooth muscle cells or collagen in aortic roots. However, there was a slight tendency towards more inflamed lesions, as demonstrated by the increase in macrophage content (4±1% vs. 6±1%, p=0.08). To test the effect of sEH-inhibition on established plaques, mice were first fed a cholesterol diet for 16 weeks and then additionally fed the diet supplemented with BIX01753 for another 8 weeks. Consistently, mice fed the sEH-inhibitor showed a reduction in lipid depositions of 20±4% as compared to the control (n=15, p=0.02).
Conclusions: We present the finding that inhibition of soluble epoxide hydrolase (sEH) concentration-dependently attenuated atherosclerotic lesions in a model of murine atherogenesis. These findings identify the soluble epoxide hydrolase as potential target in the treatment of atherosclerosis.
- © 2011 by American Heart Association, Inc.