title: Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice.
abstract: Oxidative stress is an important risk factor in the pathogenesis of atherosclerosis. Angiotensin-converting enzyme (ACE) inhibitors attenuate atherosclerosis and oxidative stress in animal models. Omapatrilat, a VasoPeptidase-inhibitor, selectively inhibits both Neutral-Endo-Peptidase (NEP) and ACE.
  
  
  OBJECTIVE
  In this study, we analyzed the effect of Omapatrilat administration (1, 4, or 20mg/kg/d, for 12 weeks) to atherosclerotic apolipoprotein E-deficient (E0) mice on their blood pressure (BP), serum and macrophage oxidative status, and atherosclerotic lesion area.
  
  
  RESULTS
  Following administration of Omapatrilat (4 mg/kg/d and 20 mg/kg/d), the mice systolic and diastolic BP significantly decreased by up to 33% and 25% respectively, compared with placebo-treated mice. However, administration of Omapatrilat at 1mg/kg/d did not affect the mice BP. The Omapatrilat-treated mice serum susceptibility to lipid peroxidation was reduced by up to 21%, and their serum paraoxonase activity was increased by up to 24%, compared with placebo-treated mice. Peritoneal macrophages from Omapatrilat-treated (20 mg/kg/d) mice exhibited a reduced oxidative stress, evidenced by a reduction in macrophage lipid peroxide content (by 45%), cholesteryl-linoleate hydroperoxide content (by 48%), and oxidized glutathione levels (by 40%). Finally, the area of the mice atherosclerotic lesion was dose-dependently reduced, by 50%, 67%, and 82%, following Omapatrilat administration at 1mg/kg/d, 4 mg/kg/d, and 20 mg/kg/d respectively, compared with placebo-treated mice.
  
  
  CONCLUSIONS
  Omapatrilat has a substantial anti-atherosclerotic effect, which can be related not only to BP reduction but also to its ability to reduce oxidative stress in atherosclerotic E0 mice.
authors.affiliation: Lipid Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion, Israel. t_hayek@rambam.health.gov.il
authors.forename: Tony
authors.initials: T
authors.lastname: Hayek
authors.forename: Shadi
authors.initials: S
authors.lastname: Hamoud
authors.forename: Shlomo
authors.initials: S
authors.lastname: Keidar
authors.forename: Elsa
authors.initials: E
authors.lastname: Pavlotzky
authors.forename: Raymond
authors.initials: R
authors.lastname: Coleman
authors.forename: Michael
authors.initials: M
authors.lastname: Aviram
authors.forename: Marielle
authors.initials: M
authors.lastname: Kaplan
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D015227:Lipid Peroxidation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018384:Oxidative Stress / Q000187:drug effects; D007703:Peptidyl-Dipeptidase A / Q000097:blood*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D013841:Thiazepines / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D001057:Apolipoproteins E; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D007703:Peptidyl-Dipeptidase A