What is the effect of hyperglycemia on atherogenesis and can it be reversed by aminoguanidine?
Reducing sugars such as glucose react non-enzymatically with the amino groups of proteins and lipids to initiate a chemical modification pathway known as advanced glycosylation. Recent progress in our understanding of this process has affirmed the hypothesis that advanced glycosylation endproducts (AGEs) play an important 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. Vascular wall AGEs contribute to vascular pathology by acting to increase vascular permeability, enhance subintimal protein and lipoprotein deposition, and inactivate the endothelium-derived relaxing factor, nitric oxide. Lipid-linked AGEs also have been shown to initiate oxidative modification, thus promoting the formation of oxidized low-density lipoprotein. AGE-specific ELISA analysis has demonstrated a significantly increased level of AGE-modified LDL in the plasma of diabetic patients when compared to normal controls. Furthermore, LDL which has been modified by advanced glycosylation exhibits markedly impaired clearance kinetics in vivo. Thus, AGE-modification impairs LDL-receptor-mediated clearance mechanisms and contributes to elevated LDL levels in patients with diabetes. This concept has been substantiated recently by the clinical observation that administration of the advanced glycosylation inhibitor aminoguanidine to diabetic patients significantly decreases circulating LDL levels.
Bucala
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Picower Institute for Medical Research, Manhasset, NY 11030, USA.
D000818:Animals; D001161:Arteriosclerosis / Q000150:complications*; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006031:Glycosylation; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000150:complications*; D050356:Lipid Metabolism; D008077:Lipoproteins, LDL / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D010084:Oxidation-Reduction
D017127:Glycation End Products, Advanced; D006146:Guanidines; D008077:Lipoproteins, LDL; C004479:pimagedine