Omapatrilat, an angiotensin-converting enzyme and neutral endopeptidase inhibitor, attenuates early atherosclerosis in diabetic and in nondiabetic low-density lipoprotein receptor-deficient mice.
Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor-deficient mice despite effective inhibition of the renin-angiotensin-aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor-deficient mice. LDL receptor-deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilat-treated nondiabetic mice was 9357 +/- 7293 microm2, versus 71977 +/- 34610 microm2 in the nontreated mice (P = .002). In the diabetic animals, the plaque area was 8887 +/- 5386 microm2 and 23220 +/- 10400 microm2, respectively for treated and nontreated mice (P = .001). Plasma lipids were increased by omapatrilat: Mean plasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 +/- 6.00 mmol/L, versus 33.12 +/- 7.64 mmol/L in the nontreated animals (P = .008). The corresponding combined mean values of triglycerides were 4.83 +/- 1.93 versus 3.00 +/- 1.26 mmol/L (P = .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor-deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall.
Levy
Zohar
Z
Department of Medicine D, Meir Hospital, Kfar-Sava, Israel.
Dvir
Ayana
A
Shaish
Aviv
A
Trestman
Svetlana
S
Cohen
Hofit
H
Levkovietz
Hana
H
Rhachmani
Rita
R
Ravid
Mordchai
M
Harats
Dror
D
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001161:Arteriosclerosis / Q000517:prevention & control*; D003921:Diabetes Mellitus, Experimental / Q000517:prevention & control*; D003925:Diabetic Angiopathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013311:Streptozocin; D013841:Thiazepines / Q000627:therapeutic use*
D000806:Angiotensin-Converting Enzyme Inhibitors; D011480:Protease Inhibitors; D011725:Pyridines; D011973:Receptors, LDL; D013841:Thiazepines; C106266:omapatrilat; D013311:Streptozocin