Ramipril administration to atherosclerotic mice reduces oxidized low-density lipoprotein uptake by their macrophages and blocks the progression of atherosclerosis.
Foam cell formation, the hallmark of early atherosclerosis, results from cholesterol accumulation in arterial macrophages. Angiotensin-II stimulates foam cell formation and angiotensin converting enzyme (ACE) inhibitors reduce atherosclerosis in animal models. The goal of the present study was to determine the effect of the ACE inhibitor Ramipril on the progression of atherosclerosis in apolipoprotein-E-deficient (E0) mice with already advanced atherosclerosis. Therefore, 4-month-old atherosclerotic E0 mice were treated with Ramipril for 2 and 4 months and compared to age-matched placebo-treated mice, as well as to control young (4-month-old) non-treated E0 mice, for their atherosclerosis. Histomorphometry showed that Ramipril treatment substantially inhibited atherogenesis as shown by 48 and 72% reduction in lesion size at 6 and 8 months of age, respectively, compared to the lesion size in age-matched placebo-treated mice. Moreover, the size of the atherosclerotic lesions in 6- and 8-month-old Ramipril-treated mice was almost identical to the size of atherosclerosis of the 4-month-old control mice. Moreover, Ramipril treatment of E0 mice, significantly reduced oxidized low-density lipoprotein (Ox-LDL) uptake by their peritoneal macrophages (MPM) by 32%, compared to Ox-LDL uptake by MPM from 6-month-old placebo mice, and even reduced it by 12% in comparison to Ox-LDL uptake by MPM from 4-month-old control mice. A significant decrease in the mRNA levels of the Ox-LDL receptor CD36 by 58% was observed in macrophages from 6-month-old Ramipril-treated mice compared to macrophages from the 6-month-old placebo-treated mice. There was even a significant reduction (by 32%) in CD36 mRNA levels in macrophages from the 6-month-old Ramipril-treated mice, compared to the CD36 mRNA levels in macrophages from the 4-month-old control mice. We thus conclude that administration of the ACE inhibitor Ramipril to E0 mice, which already exhibit significant atherosclerosis, blocked the progression of the atherosclerotic lesion build-up, a phenomenon that could be related to Ramipril-induced inhibition of Ox-LDL uptake by macrophages.
Hayek
Tony
T
The Lipid Research Laboratory, The Bruce Rappaport Faculty of Medicine, Technion, The Rappaport Family Institute for Research in the Medical Sciences and Rambam Medical Center, 31096 Haifa, Israel. t_hayek@rambam.health.gov.il
Kaplan
Marielle
M
Raz
Ayelet
A
Keidar
Shlomo
S
Coleman
Raymond
R
Aviram
Michael
M
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency; D001161:Arteriosclerosis / Q000378:metabolism* / Q000517:prevention & control; D018955:CD36 Antigens / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D005487:Foam Cells / Q000187:drug effects / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D017257:Ramipril / Q000008:administration & dosage / Q000494:pharmacology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D018955:CD36 Antigens; D008077:Lipoproteins, LDL; D012333:RNA, Messenger; C099252:oxidized low density lipoprotein; D002784:Cholesterol; D017257:Ramipril