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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:1903.)
© 2005 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Rosiglitazone Attenuates Atherosclerosis in a Model of Insulin Insufficiency Independent of Its Metabolic Effects

Anna C. Calkin; Josephine M. Forbes; Craig M. Smith; Markus Lassila; Mark E. Cooper; Karin A. Jandeleit-Dahm; Terri J. Allen

From JDRF Danielle Alberti Memorial Centre for Diabetes Complications (A.C.C., J.M.F., C.M.S., M.L., M.E.C., K.A.J.-D., T.J.A.), Vascular Division, Wynn Domain, Baker Heart Research Institute, and the Department of Medicine (A.C.C.), Monash University, Melbourne, Australia.

Correspondence to Anna C. Calkin, JDRF Danielle Alberti Centre for Diabetes Complications, Baker Heart Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne 8008, Australia. E-mail anna.calkin{at}baker.edu.au

Objectives— Recent studies have demonstrated a role for thiazolidinediones in attenuating atherosclerosis. However, these studies were performed in insulin-resistant animal models in association with reductions in insulin and glucose levels. To assess the vascular effects of thiazolidinediones, independent of their metabolic effects, we observed the effect of rosiglitazone on diabetes-associated atherosclerosis in a model of insulin insufficiency.

Methods and Results— Control and diabetic apolipoprotein E–deficient mice received rosiglitazone or placebo. Diabetic mice demonstrated a 3-fold increase in plaque area, which was attenuated by rosiglitazone. There was no significant difference in glucose, insulin, or cholesterol levels between treated and untreated diabetic animals. Rosiglitazone attenuated the increase in superoxide production observed in diabetic mice. A 4-fold increase in the reverse cholesterol transport marker ABCA1 was observed in treated diabetic mice. Rosiglitazone reduced angiotensin II receptor gene expression in control and diabetic mice, and macrophage accumulation was increased in diabetic mice compared with controls and was attenuated by rosiglitazone.

Conclusions— These findings suggest peroxisome proliferator-activated receptor- ligands such as rosiglitazone confer vascular protection independent of their effects on metabolic control. These antiatherosclerotic effects may have important clinical ramifications not only in insulin resistance/type 2 diabetes and also in type 1 diabetes.

To assess the independent vascular effects of rosiglitazone, we treated streptozotocin–diabetic apolipoprotein E–deficient mice with rosiglitazone for 20 weeks. Rosiglitazone significantly reduced plaque area in the absence of changes in glucose, insulin, or cholesterol levels. These results may implicate a role for thiazolidinediones in the absence of insulin resistance.

Key Words: ABCA1 • atherosclerosis • diabetes • macrophages • oxidative stress

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