Advanced glycation endproducts and the accelerated atherosclerosis in diabetes

The formation of advanced glycation endproducts (AGE) is an important biochemical abnormality that accompanies diabetes mellitus and, likely, inflammation. This chapter will summarize and discuss recent studies indicating that the effects of AGE on vessel wall homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes mellitus. Driven by hyperglycemia and oxidant stress, AGE form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGE may "trap" plasma proteins, quench nitric oxide activity, and interact with specific receptors to modulate many cellular properties. On plasma low-density lipoproteins (LDL), AGE initiate oxidative reactions that promote the formation of oxidized LDL. Interaction of AGE with endothelial cells and other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth muscle cells, provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGE with vessel wall components increases vascular permeability, expression of procoagulant activity, and the generation of reactive oxygen species, resulting in increased endothelial expression of endothelial leukocyte adhesion molecules. We propose that AGE potently modulate the initial steps in atherogenesis involving blood-vessel wall interactions, triggering an inflammatory-proliferative process and, furthermore, critically contribute to propagation of inflammation and vascular perturbation in established disease. Thus, a better understanding of the biochemical mechanisms by which AGE contribute to such processes in the vessel wall could be relevant to devise preventive and therapeutic strategies for diabetic atherosclerosis.