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. 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. Once developed, these mice will be bred into apo E (0) mice, which we have demonstrated to develop accelerated atherosclerosis in the setting of streptozotocin-induced diabetes. Detailed studies of the RAGE promoter will be undertaken to understand the effects of AGEs in the transcriptional/translational control of RAGE expression. They hypothesize, based on pilot studies, that overexpression of RAGE, upon exposure to AGEs, furthers the potential interactions of AGEs with RAGE, resulting in enhanced oxidant stress, favoring the development of vascular lesions. They will then examine the effects of hyperglycemia on the regulation of RAGE expression. These studies will provide new insights into the pathogenic mechanisms that underlie the accelerated atherosclerosis observed in diabetes.
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