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(Circulation Research. 2005;96:1178.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Diabetes Induces Endothelial Dysfunction but Does Not Increase Neointimal Formation in High-Fat Diet Fed C57BL/6J Mice

Judit Molnar, Shuiqing Yu, Nino Mzhavia, Clara Pau, Igor Chereshnev, Hayes M. Dansky

From the Department of Medicine (J.M., I.C.), Mount Sinai School of Medicine, New York; Department of Medicine (S.Y., N.M., C.P., H.M.D.), Columbia University Medical Center, New York

Correspondence to Dr Hayes M. Dansky, Assistant Professor of Medicine Box 93, PH-342, Columbia University Medical Center, 630 W 168th St, New York, NY 10032. E-mail hmd2101{at}columbia.edu

Studies of diabetic vascular disease have traditionally used murine models of type 1 diabetes and genetic models of type 2 diabetes. Because the majority of patients with type 2 diabetes have diet induced obesity, we sought to study the effect of diabetes on arterial disease in a mouse model of diet induced obesity/diabetes. C57Bl/6 mice fed a high-fat diet for 9 weeks developed type 2 diabetes characterized by elevated body weight, hyperglycemia, and hyperinsulinemia. Arteries from diabetic mice exhibited a marked decrease in endothelium-dependent vasodilation, a modest decrease in endothelium independent vasodilation, and an increase in sensitivity to adrenergic vasoconstricting agents. Insulin stimulated protein kinase B (akt) and endothelial nitric oxide synthase (eNOS) phosphorylation were preserved in arteries from diabetic mice; however, eNOS protein dimers were markedly diminished. Arterial nitrotyrosine staining indicated that increased levels of peroxynitrite contributed to eNOS dimer disruption in the diabetic mice. The abnormal vasomotion was not an acute response to the high-fat diet, as short term high-fat diet feeding had no effect on endothelium dependent dilation. A trend toward smaller neointimal lesions was noted in high-fat diet fed mice after femoral artery wire denudation injury. In summary, disrupted eNOS dimer formation rather than impaired insulin mediated eNOS phosphorylation contributed to the endothelial dysfunction in diet induced obese/diabetic mice. The lack of an increase in neointimal formation indicates that additional diabetes associated parameters (such as hyperlipidemia and atherosclerotic vascular disease) may need to be present to increase neointimal formation in this model.

Key Words: diabetes • mice • endothelial nitric oxide synthase • arterial injury • high-fat diet • endothelial dysfunction

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