One of the principal alterations in the diabetic milieu is the excess accumulation of proteins/lipids that have been irreversibly-modified by increased exposure to aldose sugars. The products of these interactions, known as Advanced Glycation Endproducts, or AGEs, accumulate in the vessel wall and tissues of patients with diabetes. Their enhanced presence in this disorder is believed to be important in the pathogenesis of accelerated disease of both the micro- and macrovasculature, characteristic of diabetes. One of the critical means by which AGEs interact with the vessel wall is via specific cellular receptors, the best-characterized of which is the Receptor for AGE, or RAGE. RAGE, a member of the immunoglobulin superfamily of cell surface molecules, is central in the interaction of AGEs with the cell, as our previous studies have shown that blockade of RAGE inhibits the effects of AGEs on a broad range of cells, including endothelial cells, mononuclear phagocytes and smooth muscle cells. One of the consequences of AGE-RAGE interaction is the generation of enhanced oxidant stress. Subsequent alterations in cellular phenotype then favor the development of a pro-atherogenic environment, such as enhanced expression of Vascular Cell Adhesion Molecule-I and vascular hyperpermeability. The goal of this proposal is to further dissect the role of RAGE in mediating the pro-atherogenic effects of AGEs by the development of transgenic animals that overexpress RAGE in a targeted manner, in endothelium or in mononuclear phagocytes. Detailed studies of the RAGE promoter will be undertaken to understand the effects of AGEs and oxidant stress in the transcriptionally translational control of RAGE expression. We hypothesize, based on pilot studies, that overexpression of RAGE, upon exposure to AGEs, furthers the potential interactions of AGEs with RAGE, resulting in further oxidant stress, favoring the development of vascular lesions. To further investigate this hypothesis, in collaboration with the investigators of Project #1, we will examine murine models of diabetic accelerated atherosclerosis in which inherent lipid abnormalities are not significantly altered by the diabetes in order to dissect the role of lipid-independent factors, such as AGE- RAGE interaction, in the development of advanced vascular lesions. With the investigators of Project #3, we will examine the pathologic effects of varied sizes of triglyceride-rich lipoproteins with respect to vascular perturbation. Taken together, the data derived from these projects will provide new insights into the pathogenic mechanisms that underlie the accelerated atherosclerosis observed in diabetes.
