Attenuation of accumulation of neointimal lipid by pioglitazone in mice genetically deficient in insulin receptor substrate-2 and apolipoprotein E.
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.
Clough
Maria H
MH
Department of Pathology, 89 Beaumont Avenue, College of Medicine, University of Vermont, Burlington, VT 05405, USA.
Schneider
David J
DJ
Sobel
Burton E
BE
White
Morris F
MF
Wadsworth
Marilyn P
MP
Taatjes
Douglas J
DJ
D000284:Administration, Oral; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics*; D001161:Arteriosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006949:Hyperlipidemias / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D050356:Lipid Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics*; D000077205:Pioglitazone; D011972:Receptor, Insulin / Q000378:metabolism*; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000494:pharmacology*; D017539:Tunica Intima / Q000378:metabolism* / Q000473:pathology
D001057:Apolipoproteins E; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526298:Irs2 protein, mouse; D010750:Phosphoproteins; D045162:Thiazolidinediones; D011972:Receptor, Insulin; D000077205:Pioglitazone