The effect of renin-angiotensin axis inhibition on early atherogenesis in LDL-receptor-deficient mice.
OBJECTIVE
The renin-angiotensin system may play a role in the development of atherosclerosis. Nevertheless, different results from studies attempting to attenuate the process by inhibiting the converting enzyme were equivocal, and in those who succeeded, blood pressure was lowered and/or the lipid profile was improved in addition to the inhibition of the renin-angiotensin axis. The aim of this study is to investigate the effect of low doses of fosinopril, a converting enzyme inhibitor, on the development of atherosclerosis in LDL-receptor-deficient mice.


METHODS
Three groups of 15 mice were fed a high-fat, high-cholesterol western diet. The three study groups received either distilled water (control group), or water supplemented with fosinopril 0.01 mg/kg/day (low-dose group) or with 0.1 mg/kg/day (high-dose group). Plasma aldosterone levels and lipid profiles were measured at the beginning and at the end of the study. After 10 weeks, the mice were sacrificed and the extent of atherosclerosis was assessed at the aortic sinus.


RESULTS
Plasma aldosterone levels did not change in the control group, but decreased significantly in both treated groups from 74.7 to 39.3 ng/ml in the low-dose group (p < 0.003) and from 70.7 to 33.6 ng/ml in the high-dose group (p < 0.001). The lipid profile at the end of the study showed significantly lower levels of cholesterol and triglycerides in the high-dose group as compared to the low-dose group (p < 0.05). There was no difference between the three groups regarding the area of atherosclerosis at the aortic sinus: 157,000 +/- 34,000, 130,000 +/- 58,000 and 145,000 +/- 26,000 microm(2) in the control, low-dose and high-dose groups, respectively.


CONCLUSIONS
Inhibition of the renin-angiotensin-aldosterone axis by itself does not prevent the development of early atherosclerosis in LDL-receptor-deficient mice.
Sharabi
Y
Y
Department of Medicine and Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Tel-Hashomer, 52621 Israel.
Grossman
E
E
Sherer
Y
Y
Shaish
A
A
Levkovitz
H
H
Bitzur
R
R
Harats
D
D
D000450:Aldosterone / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001161:Arteriosclerosis / Q000097:blood / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D001835:Body Weight / Q000187:drug effects; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary / Q000009:adverse effects; D017328:Fosinopril / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D012084:Renin-Angiotensin System / Q000502:physiology*; D012850:Sinus of Valsalva / Q000187:drug effects / Q000473:pathology; D014280:Triglycerides / Q000097:blood
D000806:Angiotensin-Converting Enzyme Inhibitors; D002791:Cholesterol, Dietary; D011973:Receptors, LDL; D014280:Triglycerides; D000450:Aldosterone; D002784:Cholesterol; D017328:Fosinopril