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Attenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E

Maria H. Clough, David J. Schneider, Burton E. Sobel, Morris F. White, Marilyn P. Wadsworth and Douglas J. Taatjes

Departments of Pathology (MHC,MPW,DJT) and Medicine (DJS,BES,DJT) and Microscopy Imaging Center (MHC,MPW,DJT), College of Medicine, University of Vermont, Burlington, Vermont, and Howard Hughes Medical Institute, Joslin Diabetes Center, Harvard Medical School, Boston, MA (MFW)

Correspondence to: Dr. Douglas J. Taatjes, Department of Pathology, 89 Beaumont Avenue, College of Medicine, University of Vermont, Burlington, VT 05405. E-mail: douglas.taatjes{at}uvm.edu

Rupture of vulnerable atherosclerotic plaques that are characterized by extensive neointimal accumulation of lipid is a cause of acute coronary syndromes. To identify whether insulin resistance alters atherogenesis, we characterized the composition of atherosclerotic lesions in the proximal aortas in mice deficient in apolipoprotein E (ApoE^–/–) and in ApoE^–/– mice in which insulin resistance was intensified by a concomitant heterozygous deficiency in insulin receptor substrate type 2 (IRS2^+/– ApoE^–/– mice). In addition, we characterized the effect of an insulin sensitizer, pioglitazone, on the atherogenesis in IRS2^+/– ApoE^–/– mice. The extent of the aortic intima occupied by lesion was increased in the IRS2^+/– ApoE^–/– compared with ApoE^–/– mice (79 ± 3% compared with 68 ± 8%, p<0.05). Treatment with pioglitazone decreased the neointimal content of lipid in 20-week-old mice from 50 ± 6% to 30 ± 7%, p=0.005 and decreased the cellularity reflected by the multisection cross-sectional areas of lesions comprising cells in atheroma from 24 ± 1% to 19 ± 3%, p=0.018. Accordingly, genetically induced intensification of insulin resistance increases atheroma formation. Furthermore, attenuation of insulin resistance by treatment with pioglitazone decreases accumulation of lipid in the neointima.

(J Histochem Cytochem 53:603–610, 2005)

Key Words: pioglitazone • neointima • atherosclerosis • transgenic mice • insulin receptor substrate • plaque composition • lipid • insulin resistance • image analysis

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