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

Circulation. 2002 Jul 9;106(2):246-53. doi: 10.1161/01.cir.0000021122.63813.32.


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.

Methods and 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • 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
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / chemistry
  • Peptidyl-Dipeptidase A / genetics
  • Peptidyl-Dipeptidase A / metabolism
  • Perindopril / therapeutic use*
  • Phagocytes / physiology
  • Proliferating Cell Nuclear Antigen / analysis
  • RNA, Messenger / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / biosynthesis
  • Vascular Cell Adhesion Molecule-1 / genetics


  • Actins
  • Angiotensin-Converting Enzyme Inhibitors
  • Apolipoproteins E
  • CCN2 protein, mouse
  • Growth Substances
  • Immediate-Early Proteins
  • Intercellular Signaling Peptides and Proteins
  • Proliferating Cell Nuclear Antigen
  • RNA, Messenger
  • Vascular Cell Adhesion Molecule-1
  • Connective Tissue Growth Factor
  • Collagen
  • Peptidyl-Dipeptidase A
  • Perindopril