Forum: Role of Oxidation in Atherosclerosis GLYCOXIDATION AND LIPOXIDATION IN ATHEROGENESIS

Abstract—Atherosclerosis may be viewed as an age-related disease initiated by nonenzymatic, chemical reactions in a biological system. The peroxidation of lipids in lipoproteins in the vascular wall leads to local production of reactive carbonyl species that mediate recruitment of macrophages, cellular activation and proliferation, and chemical modifi-cation of vascular proteins by advanced lipoxidation end-products (ALEs). The ALEs and their precursors affect the structure and function of the vascular wall, setting the stage for atherogenesis. The increased risk for atherosclerosis in diabetes may result from additional carbonyl production from carbohydrates and additional chemical modification of proteins by advanced glycation end-products (AGEs). Failure to maintain homeostasis and the increase in oxidizable substrate (lipid) alone, rather than oxidative stress, is the likely source of the increase in reactive carbonyl precursors and the resultant ALEs and AGEs in atherosclerosis. Nucleophilic AGE-inhibitors, such as aminoguanidine and pyridoxamine, which trap reactive carbonyls and inhibit the formation of AGEs in diabetes, also trap bioactive lipids and precursors of ALEs in atherosclerosis. These drugs should be effective in retarding the development of athero