The goal of this program project is to better understand the excess atherosclerotic cardiovascular disease (ASCVD) associated with diabetes mellitus. Experiments will be conducted in three projects using a range of methodologies and models, including transgenic mice, tissue culture and human clinical studies. The major, unifying theme of the proposed studies focuses on the effects of chronic hyperglycemia and dyslipidemia as etiologic factors in the accelerated development of ASCVD in diabetic patients. Project 1 will use transgenic (Tg) mouse models with and without diabetes to test the hypothesis that the atherogenicity of triglyceride- rich lipoproteins (TGRL) depends on number, size and composition. Apoprotein EO and apoB Tg mice, overexpressing apoB to varying de will be studied alone and after crossing with apoC or apo Cl Tg mice. These crosses will produce dyslipidemia with TGRL that vary greatly in size and number. The degree of atherosclerosis in these animals will be measured in the absence or presence of diabetes. Project 2 will use apoEO and apoB Tg mice to study the role of advanced glycation endproducts (AGE) and the Receptor for AGE (RAGE) in the development of atherosclerosis. Tissue specific RAGE Tg mice overexpressing the receptor in endothelial cells or macrophages will be used. These mice will be crossed with the optimal model of accelerated diabetic atherosclerosis in the setting of minimal lipid changes (defined in Project 1) so as to better define the interaction of AGE, RAGE, and dyslipidemia. Projects 1 and 2 will interact closely in studies designed to distinguish between the effects of dyslipidemia and chronic hyperglycemia. Project 3 will test hypotheses concerning the atherogenicity of TGRL in several human populations. A case-control study o diabetics with or without CAD will determine if TGRL size and number differ between the groups. TGRL size and number will also be compared in diabetics with and without carotid atherosclerosis in the ARIC study, in Sioux and Pima Indians with NIDDM in the Strong Heart Study, and in Blacks, Whites and Hispanics with IGT and NIDDM in the IRAS study. Project 3 will interact with Projects 1 and 2 in experiments of the effects of different size TGRL on markers of endothelial dysfunction. A Lipoprotein and Apoprotein Core will ensure efficient endpoint measurements in all projects. At the end of this PROGRAM PROJECT, we expect to have generated new and important information related to the accelerated development of ASCVD in diabetics. This will allow for better prevention and more specific intervention in this patient population.
