title: Prevention of accelerated atherosclerosis by angiotensin-converting enzyme inhibition in diabetic apolipoprotein E-deficient mice.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Medicine, University of Melbourne, Austin and Repatriation Medical Centre, Heidelberg West, Australia.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Candido
authors.forename: Karin A
authors.initials: KA
authors.lastname: Jandeleit-Dahm
authors.forename: Zemin
authors.initials: Z
authors.lastname: Cao
authors.forename: Stefan P
authors.initials: SP
authors.lastname: Nesteroff
authors.forename: Wendy C
authors.initials: WC
authors.lastname: Burns
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Twigg
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Dilley
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Terri J
authors.initials: TJ
authors.lastname: Allen
mesh_terms: D000199:Actins / Q000032:analysis; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D001011:Aorta / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D003094:Collagen / Q000032:analysis; D055513:Connective Tissue Growth Factor; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D018450:Disease Progression; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D017874:Immediate-Early Proteins / Q000096:biosynthesis / Q000235:genetics; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000737:chemistry; D007703:Peptidyl-Dipeptidase A / Q000235:genetics / Q000378:metabolism; D020913:Perindopril / Q000627:therapeutic use*; D010586:Phagocytes / Q000502:physiology; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D012333:RNA, Messenger / Q000096:biosynthesis; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics
chemical_list: D000199:Actins; D000806:Angiotensin-Converting Enzyme Inhibitors; D001057:Apolipoproteins E; C526318:CCN2 protein, mouse; D006133:Growth Substances; D017874:Immediate-Early Proteins; D036341:Intercellular Signaling Peptides and Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; D055513:Connective Tissue Growth Factor; D003094:Collagen; D007703:Peptidyl-Dipeptidase A; D020913:Perindopril