Numerous reports document the presence of lysyl-adducts of glucose and oxidized lipids in the extracellular matrix of blood vessels. The proteins that are modified in these locations are long-lived and accumulate over time. Data from Dr. Silverstein's laboratory indicates that lysyl-adducts in the extracellular matrix are ligands for Class A scavenger receptors on mononuclear phagocytes and for scavenger-like receptors on endothelial cells. Dr. Silverstein and his colleagues suggest that interactions on scavenger-like receptors of endothelial cells and scavenger receptors of endothelial cells. Dr. Silverstein and his colleagues suggest that interactions on scavenger-like receptors of endothelial cells and scavenger receptors or mononuclear phagocytes with basement membrane proteins whose residues are altered by oxidized lipids (oxLDL) or glucose promote changes in these cells that initiate and result in the progression of atherosclerotic lesions. This hypothesis is unique in two respects: First, it postulates that modification of arterial matrix proteins is the """"""""injury"""""""" that initiates atherogenesis. Second, it proposes a common mechanism for the pathogenesis of atherosclerosis associated with hyperglycemia and hypercholesterolemia. My goal in this study is to examine the effects of glucose and/or oxLDL modified extracellular matrix proteins on gene expression in endothelial cells and mononuclear phagocytes. However, in order to establish the most ideal conditions for this study, I will first determine the effects of modified matrices on specific endothelial cells and mononuclear phagocytic functions (i.e. endothelial monolayer permeability and macrophage foam cell formation) and then examine the ability of these cells to modify extracellular matrix.
