Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein E-knockout mouse model

Arzu Ulu, Benjamin B. Davis, Hsing Ju Tsai, In Hae Kim, Christophe Morisseau, Bora Inceoglu, Oliver Fiehn, Bruce D. Hammock, Robert H Weiss

Research output: Contribution to journalArticle

98 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)314-323
Number of pages10
JournalJournal of Cardiovascular Pharmacology
Volume52
Issue number4
DOIs
StatePublished - Oct 2008

Keywords

  • 1-adamantan-3-(5-(2-(2-ethylethoxy)ethoxy)pentyl) urea
  • Apo E knockout mice
  • Atherosclerosis
  • Epoxyeicosatrienoic acid
  • Soluble epoxide hydrolase

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

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