title: Inhibition of soluble epoxide hydrolase attenuated atherosclerosis, abdominal aortic aneurysm formation, and dyslipidemia.
abstract: OBJECTIVE
  Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore 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 aimed to test the hypothesis that inhibition of s-EH has vascular protective effects.
  
  
  RESULTS
  Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) 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 (1.5 g/L 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 lipid, IL-6, murine IL-8-KC, and IL-1alpha, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall.
  
  
  CONCLUSIONS
  The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.
authors: Arête Therapeutics Inc, 3912 Trust Way, Hayward, CA 94545, USA. lzhang@aretetherapeutics.com
authors: Le-Ning
authors: LN
authors: Zhang
authors: Jon
authors: J
authors: Vincelette
authors: Ying
authors: Y
authors: Cheng
authors: Upasana
authors: U
authors: Mehra
authors: Dawn
authors: D
authors: Chen
authors: Sampath-Kumar
authors: SK
authors: Anandan
authors: Richard
authors: R
authors: Gless
authors: Heather K
authors: HK
authors: Webb
authors: Yi-Xin Jim
authors: YX
authors: Wang
mesh_terms: D000284:Administration, Oral; D000804:Angiotensin II; D000818:Animals; D017544:Aortic Aneurysm, Abdominal / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D001682:Biological Availability; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000601:surgery; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D015536:Down-Regulation; D050171:Dyslipidemias / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D053582:Interleukin-1alpha / Q000097:blood; D015850:Interleukin-6 / Q000097:blood / Q000235:genetics; D016209:Interleukin-8 / Q000097:blood; D008026:Ligation; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D053582:Interleukin-1alpha; D015850:Interleukin-6; D016209:Interleukin-8; D019010:Vascular Cell Adhesion Molecule-1; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; D002784:Cholesterol; D004851:Epoxide Hydrolases