Omapatrilat decreased macrophage oxidative status and atherosclerosis progression in atherosclerotic apolipoprotein E-deficient mice.
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.
Hayek
Tony
T
Lipid Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion, Israel. t_hayek@rambam.health.gov.il
Hamoud
Shadi
S
Keidar
Shlomo
S
Pavlotzky
Elsa
E
Coleman
Raymond
R
Aviram
Michael
M
Kaplan
Marielle
M
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
D001057:Apolipoproteins E; D011480:Protease Inhibitors; D011725:Pyridines; D013841:Thiazepines; C106266:omapatrilat; D007703:Peptidyl-Dipeptidase A