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Diabetes and Arterial Extracellular Matrix Changes in a Porcine Model of Atherosclerosis

Thomas O. McDonald, Ross G. Gerrity, Christy Jen, Hao-Ji Chen, Kathleen Wark, Thomas N. Wight, Alan Chait and Kevin D. O'Brien

Divisions of Cardiology (TOM,CJ,H-JC,KW,KDO) and Metabolism, Endocrinology, and Nutrition (AC), Department of Medicine, University of Washington, Seattle, Washington; Department of Pathology, Medical College of Georgia, Augusta, Georgia (RGG); and Hope Heart Program at the Benaroya Research Institute, Seattle, Washington (TNW)

Correspondence to: Kevin D. O'Brien, MD, Division of Cardiology, Box 356422, University of Washington, Seattle, WA 98195-6422. E-mail: cardiac{at}u.washington.edu

Patients with diabetes are at substantially increased risk for atherosclerosis and clinical cardiovascular events. Because arterial extracellular matrix contains several molecules, including biglycan, versican, hyaluronan, and elastin, that may affect plaque lipid retention and stability, we determined whether diabetes affects plaque content of these molecules in a porcine model of hyperlipidemia and diabetes. Coronary artery sections were studied from non-diabetic normolipidemic (n=11, N-NL), diabetic normolipidemic (n=10, DM-NL), non-diabetic hyperlipidemic (n=16, N-HL), and diabetic hyperlipidemic (n=15, DM-HL) animals. Hyaluronan, biglycan, versican, and apolipoprotein B (apoB) were detected with monospecific peptides or antisera, and elastin with Movat's pentachrome stain, and contents of each were quantified by computer-assisted morphometry. In the hyperlipidemic groups, diabetes was associated with a 4-fold increase in intimal area, with strong correlations between intimal area and immunostained areas for hyaluronan (R² = 0.83, p<0.0001), biglycan (R² = 0.72, p<0.0001), and apoB (R² = 0.23, p=0.0069). In contrast, median (interquartile range) intimal elastin content was significantly lower with diabetes [N-HL: 5.2% (2.4–8.2%) vs DM-HL: 1.5% (0.5–4.2%), p=0.01], and there was a strong negative correlation between intimal total and elastin areas (Spearman r = –0.62, p=0.001). In this porcine model, diabetes was associated with multiple extracellular matrix changes that have been associated with increased lesion instability, greater atherogenic lipoprotein retention, and accelerated atherogenesis. (J Histochem Cytochem 55:1149–1157, 2007)

Key Words: diabetes • atherosclerosis • extracellular matrix • hyaluronan • biglycan • versican • apolipoprotein • elastin

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