Protein glycosylation and the pathogenesis of atherosclerosis

This review summarizes the progress of research in nonenzymatic glycosylation that is of potential relevance to atherosclerosis and relates this knowledge to the accelerated large-vessel disease observed in diabetics through a hypothetical model based on current concepts of atherogenesis. Critical new information has recently been obtained about complex glycosylation adducts, which form very slowly through a series of further reactions and rearrangements from the initial Amadori product. These adducts, called advanced glycosylation end products (AGE), are not reversible like the Amadori product. Thus, they continue to accumulate indefinitely on long-lived molecules such as collagen and nucleic acids. AGE covalently trap soluble plasma proteins, act as signals for macrophage recognition and uptake, and induce mutations in double-stranded plasmid DNA. Covalent trapping of low-density lipoproteins by AGE on collagen may promote excessive lipid accumulation in the arterial walls of diabetics, whereas trapping of von Willebrand factor by AGE may increase platelet adhesion and aggregation, leading to smooth muscle cell proliferation in the arterial intima. Recognition and uptake of AGE-protein derivatives by scavenging macrophages may further contribute to the process of atherogenesis by stimulating the release of such macrophage secretory products as macrophage-derived growth factor. Accumulation of AGE on smooth muscle cell DNA may also enhance proliferation of arterial smooth muscle cells by increasing the rate of mutations that affect growth control.