Advanced glycosylation endproducts: Role in diabetic and non‐diabetic vascular disease

Reducing sugars such as glucose react non‐enzymatically with the amino groups of macromolecules to initiate a chemical modification process known as advanced glycosylation. This pathway proceeds from reversible Schiff base adducts to a heterogenous group of irreversibly‐bound, cross‐linking moieties called advanced glycosylation endproducts or AGEs. Recent progress in our understanding of this process in vivo has affirmed the hypothesis that AGEs play an intimate role in the evolution of both diabetic and non‐diabetic vascular disease. Utilizing newly developed AGE‐specific ELISA techniques, AGEs have been identified to be present on a variety of vascular wall, lipoprotein, and lipid constituents. Protein‐bound AGEs, for example, contribute to a variety of pathological effects in vivo by acting to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, and exert direct toxic effects on endothelial cells. Lipid‐AGEs promote oxidative modification and may contribute to atherogenesis by initiating the formation of oxidized low density lipoprotein (ox‐LDL). Aminoguanidine, a recently developed pharmacological inhibitor of advanced glycosylation, is presently undergoing phase II clinical trials and may offer a specific therapeutic modality for the treatment of pathological conditions that result from excessive advanced glycosylation.