Chronic treatment with sulfhydryl angiotensin-converting enzyme inhibitors reduce susceptibility of plasma LDL to in vitro oxidation, formation of oxidation-specific epitopes in the arterial wall, and atherogenesis in apolipoprotein E knockout mice.
The effects of chronic treatment with the new sulfhydryl angiotensin-converting enzyme (ACE)-inhibitor, zofenopril, in comparison with the classical sulfhydryl ACE-inhibitor captopril or enalapril or placebo on the development of atherosclerosis were determined in apolipoprotein-E knockout (apoE(-/-)) mice. Groups of 2-month-old male mice received either placebo (N=10), 0.05 mg/kg/day of zofenopril (N=10), 1 mg/kg/day of zofenopril (N=10), 5 mg/kg/day of captopril (N=10) or 0.5 mg/kg/day of enalapril (N=8). After 29 weeks of treatment, computer-assisted imaging analysis revealed that zofenopril reduced the aortic cumulative lesion area by 78% at 0.05 mg/kg/day and by 89% at 1 mg/ml/day of zofenopril compared to that of the placebo (P<0.0001). Captopril reduced by 52% aortic lesions compared to placebo (P<0.01 vs. placebo; P<0.05 vs. zofenopril at both doses). Enalapril did not reduce aortic lesions. Furthermore, 0.05 mg/kg/day of zofenopril reduced susceptibility of plasma LDL to in vitro oxidation compared to captopril, enalapril or placebo, as shown by significant reduction of malondialdehyde content (P<0.001 vs. placebo or enalapril; P<0.05 vs. captopril), as well as by the prolongation of lag-time (P<0.01 vs. placebo or enalapril P<0.05 vs. captopril). More importantly, mice treated with 1 mg/ml/day of zofenopril had a significant decrease in the intimal immunohistochemical presence of oxidation-specific epitopes on oxLDL (NA59 monoclonal antibody, P<0.01), macrophages derived foam cells (F4/80 monoclonal antibody, P<0.05) and native LDL (NP monoclonal antibody, P<0.01) compared to placebo, captopril or enalapril. Thus, chronic treatment with the new sulfhydryl ACE-inhibitor zofenopril has antiatherosclerotic and antioxidant effects in the arterial wall of hypercholesterolemic apoE(-/-) mice. This protection was significantly higher than that reached with captopril and at lower doses of the drug. Treatment with 0.5 mg/kg/day of enalapril did not provide any protective effect.
de Nigris
F
F
Department of Medicine, School of Medicine, University of Naples, P.O. Box 80131, Naples, Italy.
D'Armiento
F P
FP
Somma
P
P
Casini
A
A
Andreini
I
I
Sarlo
F
F
Mansueto
G
G
De Rosa
G
G
Bonaduce
D
D
Condorelli
M
M
Napoli
C
C
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001024:Aortic Valve Stenosis / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D001057:Apolipoproteins E / Q000187:drug effects*; D001158:Arteries / Q000737:chemistry / Q000187:drug effects*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000627:therapeutic use; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000627:therapeutic use; D000939:Epitopes / Q000378:metabolism; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects*; D008077:Lipoproteins, LDL / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000187:drug effects; D011897:Random Allocation; D013439:Sulfhydryl Reagents / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; D000939:Epitopes; D008077:Lipoproteins, LDL; D013439:Sulfhydryl Reagents; C099252:oxidized low density lipoprotein; C044958:zofenopril; D004656:Enalapril; D002784:Cholesterol; D002216:Captopril; D007703:Peptidyl-Dipeptidase A