THE ROLE OF ADVANCED GLYCOSYLATION END-PRODUCTS IN THE PATHOGENESIS OF ATHEROSCLEROSIS

Coronary artery disease and cerebrovascular disease due to the rapid p rogression of atherosclcrosis is the principal cause of death in diabe tes mellitus. Modification of low-density lipoproteins (LDL) by advanc ed glycosylation end-products (AGE) may play a central role in the dev elopment of atherosclerosis, especially in diabetic patients. An AGE-m odified form of LDL (AGE-LDL) has been found to circtulate in human pl asma, and AGE modifications have been identified as being present on b oth the apoprotein (ApoB) and the phospholipid components of LDL. By u tilizing an AGE-specific ELISA, we measured the AGE attached to the Ap oB and lipid components of LDL from normal controls and diabetic patie nts with or without end-stage renal disease (ESRD), as well as lipid o xidation. AGE-ApoB, AGE-lipid and oxidized LDL (Ox-LDL) in diabetic pa tients were significantly higher than those in patients without diabet es. The correlation between AGE-ApoB and AGE-lipid were highly signifi cant. An especially marked elevation of AGE-LDL was found in diabetic patients with ESRD. The correlation between the serum total cholestero l and the AGE-LDL (AGE-ApoB and AGE-lipid) was significant. In additio n, based on the known biological properties of AGE-modified peptide (A GE-peptide), we have proposed that these chemically reactive circulati ng AGE-peptides contribute to tissue injury by reattaching to suscepti ble target proteins both within and outside the vasculature, and that this process accelerates vascular pathology in diabetic patients. Thes e data indicate that AGE-modified LDLs may represent a particularly at herogenic form of LDL, and AGE-LDLs as well as AGE-peptides are likely to contribute to the development of atherosclerosis in diabetic patie nts.