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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:2250-2256.)
© 1997 American Heart Association, Inc.

Articles

Effect of Streptozotocin-Induced Hyperglycemia on Lipid Profiles, Formation of Advanced Glycation Endproducts in Lesions, and Extent of Atherosclerosis in LDL Receptor-Deficient Mice

Peter Reaven; Shiva Merat; Florencia Casanada; Mary Sutphin; ; Wulf Palinski

From the Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, California.

Correspondence to Peter Reaven, MD, Division of Endocrinology and Metabolism, Department of Medicine, 0682, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093-0682.

Abstract Investigations into the mechanisms by which diabetes accelerates atherosclerosis have been hampered by the lack of suitable animal models. We hypothesized that streptozotocin-treated LDL receptor-deficient mice would be a good model of diabetic atherosclerosis because streptozotocin causes diabetes in the parent C57BL/6 strain and because in these mice diet-induced hypercholesterolemia leads to the formation of advanced atherosclerotic lesions throughout the aorta. Diabetes was induced in 18 mice by intraperitoneal injection of streptozotocin. Low-dose insulin was given subcutaneously to prevent excessive mortality and extreme elevations in triglyceride levels. The control group was subjected to sham injections. Both groups were fed a diet containing .075% cholesterol for six months. Average blood glucose was higher in the diabetic group than in the control group (257±67 mg/dL versus 111±7 mg/dL, P<0.05). Although plasma cholesterol was similar (966±399 versus 1002±180 mg/dL) in both groups, VLDL cholesterol was higher whereas LDL cholesterol was lower in the diabetic group. Immunocytochemical analysis demonstrated significantly more advanced glycation endproduct (AGE) epitopes in the artery wall of the diabetic group, whereas staining for oxidation-specific epitopes was similar in both groups. Sera of diabetic mice also contained significantly more IgG autoantibodies that bound to several AGE epitopes than did sera from control mice. Despite the presence of hyperglycemia, diabetic dyslipidemia, and enhanced AGE formation in the diabetic mice, both groups had a similar extent of atherosclerosis (diabetic, 17.3±5.2; control, 16.5±6.6% of the aortic surface). These data suggest that, at least under conditions of marked hypercholesterolemia, hyperglycemia and enhanced AGE formation do not contribute significantly to atherogenesis in LDL^-/- mice.

Key Words: arteriosclerosis • advanced glycation endproducts • diabetes • autoantibodies • lipid peroxidation • LDL oxidation

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