Sustained, local endothelial dysfunction and monocyte activation contribute importantly to the pathogenesis of atherosclerosis. Advanced Glycation Endproducts (AGEs) accumulate in atherosclerotic lesions, and, to an even greater extent with concomitant glucose tolerance and/or renal failure. The proximity of vessel wall AGEs to cellular elements of the vasculature, along with the known capacity of these non-enzymatically glycated adducts to modulate properties of endothelial cells (Ecs) and mononuclear phagocytes (MPs), has emphasized the importance of analyzing in molecular terms the basis of AGE-cellular interactions. We have identified and characterized Receptor for AGE (RAGE), which serves as a cell surface acceptor site for AGEs on ECs and MPs: antagonism of AGE-RAGE interaction blocks effects of AGEs on cellular targets. We hypothesize that AGE engagement of RAGE on endothelial cells and mononuclear phagocytes produces sustained cellular activation which underlies the enhanced development of atherosclerosis in vascular beds rich in AGEs. Our pilot studies have employed euglycemic and glucose-intolerant apoE mull (o) mice, to provide an AGE-rich vascular microenvironment; insulin- deficient apoE mice showed accelerated atherosclerosis compared with euglycemic controls, and antagonism of AGE-RAGE interaction suppressed lesion formation.
The specific aims of Project 1 further testing the concept that AGE binding to RAGE underlies vascular lesion formation; (2) to extend our concept of accelerated vascular lesions associated with AGEs to a model of insulin resistance (transgenic [Tg] UCP-DTA mice), and to study Tg apoB mice in order to extrapolate our concept to a murine system in which the lipoprotein profile more closely resembles that in man; and, (3) to determine factors underlying the increased expression of RAGE at the site of vascular-lesions. Project 1 will work closely with Projects 2- 3 and will obtain technical assistance from the Cores A, B and C. Collaborative interactions include: provision of Tg RAGE mice (Projects 2- 3 and Core C), cytokine and collagen/collagenase analysis (Projects 2-3), mapping the ligand binding domain of RAGE (Project 2), and pathologic analysis (Core B).
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