RAGE, Diabetes, &Accelerated Atherosclerosis

A major cause of morbidity and mortality in subjects with diabetes is accelerate atherosclerosis and vascular function. Previous studies identified that blockade of Receptor for AGE (RAGE) in diabetic apo E null mice prevented the development of accelerated atherosclerosis and halted the progression of established lesions. Here, we propose to dissect the contribution of RAGE and RAGE-bearing cells in these procedures by employing mice homozygously null for RAGE bred into the apo E null background, as well as transgenic mice with targeted expression of dominant negative RAGE in the apo E null background in monocytes, endothelial cells and vascular smooth muscle cells. Induction of diabetes in these different animal models will allow us to study the role and contribution of RAGE in key cells limited to inflammatory and migratory events that are essential in atherosclerotic lesion development and progression. We propose that examination of RAE in these mice will provide new insights into mechanisms by which blockade of the receptor affords beneficial results in diabetic atherosclerosis in murine models; components of which, at least in part, be directly translated to human disease.