The role of advanced glycosylation end-products in the pathogenesis of atherosclerosis.
Coronary artery disease and cerebrovascular disease due to the rapid progression of atherosclerosis is the principal cause of death in diabetes mellitus. Modification of low-density lipoproteins (LDL) by advanced glycosylation end-products (AGE) may play a central role in the development of atherosclerosis, especially in diabetic patients. An AGE-modified form of LDL (AGE-LDL) has been found to circulate in human plasma, and AGE modifications have been identified as being present on both the apoprotein (ApoB) and the phospholipid components of LDL. By utilizing an AGE-specific ELISA, we measured the AGE attached to the ApoB and lipid components of LDL from normal controls and diabetic patients with or without end-stage renal disease (ESRD), as well as lipid oxidation. AGE-ApoB, AGE-lipid and oxidized LDL (Ox-LDL) in diabetic patients were significantly higher than those in patients without diabetes. The correlation between AGE-ApoB and AGE-lipid were highly significant. An especially marked elevation of AGE-LDL was found in diabetic patients with ESRD. The correlation between the serum total cholesterol and the AGE-LDL (AGE-ApoB and AGE-lipid) was significant. In addition, based on the known biological properties of AGE-modified peptide (AGE-peptide), we have proposed that these chemically reactive circulating AGE-peptides contribute to tissue injury by reattaching to susceptible target proteins both within and outside the vasculature, and that this process accelerates vascular pathology in diabetic patients. These data indicate that AGE-modified LDLs may represent a particularly atherogenic form of LDL, and AGE-LDLs as well as AGE-peptides are likely to contribute to the development of atherosclerosis in diabetic patients.
Makita
Z
Z
Hokkaido University, School of Medicine, Sapporo, Japan.
Yanagisawa
K
K
Kuwajima
S
S
Bucala
R
R
Vlassara
H
H
Koike
T
T
D001055:Apolipoproteins B / Q000378:metabolism; D001161:Arteriosclerosis / Q000209:etiology* / Q000378:metabolism*; D002561:Cerebrovascular Disorders / Q000209:etiology / Q000378:metabolism; D003327:Coronary Disease / Q000209:etiology / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism*; D003928:Diabetic Nephropathies / Q000150:complications / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism
D001055:Apolipoproteins B; D017127:Glycation End Products, Advanced; D008077:Lipoproteins, LDL