Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice

• Published in: Circulation (New York, N.Y.) N.Y.), 2002-07, Vol.106 (2), p.246-253
• Main Authors: CANDIDO, Riccardo, JANDELEIT-DAHM, Karin A, ZEMIN CAO, NESTEROFF, Stefan P, BURNS, Wendy C, TWIGG, Stephen M, DILLEY, Rodney J, COOPER, Mark E, ALIEN, Terri J
• Format: Article
• Language: English
• Subjects: Actins - analysis; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Animals; Aorta - chemistry; Aorta - metabolism; Aorta - pathology; Apolipoproteins E - genetics; Arteriosclerosis - etiology; Arteriosclerosis - metabolism; Arteriosclerosis - pathology; Arteriosclerosis - prevention & control; Biological and medical sciences; Cardiovascular system; Collagen - analysis; Connective Tissue Growth Factor; Diabetes Mellitus, Experimental - complications; Disease Progression; Growth Substances - biosynthesis; Growth Substances - genetics; Immediate-Early Proteins - biosynthesis; Immediate-Early Proteins - genetics; Intercellular Signaling Peptides and Proteins; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular - chemistry; Peptidyl-Dipeptidase A - genetics; Peptidyl-Dipeptidase A - metabolism; Perindopril - therapeutic use; Phagocytes - physiology; Pharmacology. Drug treatments; Proliferating Cell Nuclear Antigen - analysis; RNA, Messenger - biosynthesis; Vascular Cell Adhesion Molecule-1 - biosynthesis; Vascular Cell Adhesion Molecule-1 - genetics; Vasodilator agents. Cerebral vasodilators
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.0000021122.63813.32

Atherosclerosis is a major complication of diabetes, but the mechanisms by which diabetes promotes macrovascular disease have not been fully delineated. Although several animal studies have demonstrated that inhibition of ACE results in a decrease in the development of atherosclerotic lesions, information about the potential benefits of these agents on complex and advanced atherosclerotic lesions as observed in long-term diabetes is lacking. The aim of this study was to evaluate whether treatment with the ACE inhibitor perindopril affects diabetes-induced plaque formation in the apolipoprotein E (apoE)-deficient mouse. Diabetes was induced by injection of streptozotocin in 6-week-old apoE-deficient mice. Diabetic animals received treatment with perindopril (4 mg x kg(-1) x d(-1)) or no treatment for 20 weeks. Nondiabetic apoE-deficient mice were used as controls. Induction of diabetes was associated with a 4-fold increase in plaque area compared with nondiabetic animals. This accelerated atherosclerosis was associated with a significant increase in aortic ACE expression and activity and connective tissue growth factor and vascular cell adhesion molecule-1 expression. Perindopril treatment inhibited the development of atherosclerotic lesions and diabetes-induced ACE, connective tissue growth factor, and vascular cell adhesion molecule-1 overexpression in the aorta. The activation of the local renin-angiotensin system in the diabetic aorta and the reduction in atherosclerosis with ACE inhibitor treatment provides further evidence that the renin-angiotensin system plays a pivotal role in the development and acceleration of atherosclerosis in diabetes.