title: Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein e-knockout mouse model.
abstract: To determine whether sEH inhibitors influence atherosclerotic lesion formation, we used an established murine model of accelerated atherogenesis, ApoE knockout (-/-) mice. The sEH inhibitor, 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl)urea (AEPU) was delivered in drinking water. All animals were fed an atherogenic diet while simultaneously infused with angiotensin II by osmotic minipump to induce atherosclerosis. In AEPU-treated animals, there was a 53% reduction in atherosclerotic lesions in the descending aortae as compared to control aortae. AEPU and its major metabolites were detected in the plasma of animals which received it. As expected from the inhibition of sEH, a significant increase in linoleic and arachidonic acid epoxides, as well as an increase in individual 11,12-EET/DHET and 14,15-EET/DHET ratios, were observed. The reduction in atherosclerotic lesion area was inversely correlated with 11,12- and 14,15- EET/DHET ratios, suggesting that the reduction corresponds to the inhibition of sEH. Our data suggest that orally-available sEH inhibitors may be useful in the treatment of patients with atherosclerotic cardiovascular disease.
authors.affiliation: Department of Entomology, University of California Davis, CA, USA.
authors.forename: Arzu
authors.initials: A
authors.lastname: Ulu
authors.forename: Benjamin B
authors.initials: BB
authors.lastname: Davis
authors.forename: Hsing-Ju
authors.initials: HJ
authors.lastname: Tsai
authors.forename: In-Hae
authors.initials: IH
authors.lastname: Kim
authors.forename: Christophe
authors.initials: C
authors.lastname: Morisseau
authors.forename: Bora
authors.initials: B
authors.lastname: Inceoglu
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Hammock
authors.forename: Robert H
authors.initials: RH
authors.lastname: Weiss
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D004036:Diet, Atherogenic; D004195:Disease Models, Animal; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D015394:Molecular Structure; D008970:Molecular Weight; D010865:Pilot Projects; D012995:Solubility
chemical_list: D001057:Apolipoproteins E; D000804:Angiotensin II; D004851:Epoxide Hydrolases
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