Advanced glycation end-products and atherosclerosis.
The late rearrangements of the covalent nonenzymatic modification of proteins by glucose, called advanced glycation end-products (AGEs), have been shown to accumulate in diabetic and ageing tissues. AGEs elicit a wide range of cell-mediated responses leading to vascular dysfunction, matrix expansion and athero- and glomerulosclerosis. Cellular responses are thought to be largely induced through an AGE-specific cell-surface receptor complex (AGEr). Interaction of AGE-modified proteins with these cells may serve diverse purposes, including disposal of senescent AGE-modified molecules and initiation of tissue repair and protein turnover. In humans, the normal renal clearance rate for the AGE-degradation products found in serum, AGE peptides (AGEp), correlates inversely with renal creatinine clearance rate. Of note, circulating AGEp include reactive intermediates which readily attach covalently to either insoluble matrix collagen or serum proteins, e.g. low-density lipoproteins (LDL), to form AGEp collagen and AGEp-LDL. Consistent with this, diabetic and nondiabetic patients with renal failure (a group highly susceptible to accelerated atherosclerosis) exhibit markedly elevated AGE-modified serum LDL. In summary, in addition to glucose-derived AGEs, the endogenously produced degradation products, AGE peptides, can amplify tissue damage and thus account as distinct toxins. The effects may particularly accelerate glucose toxicity in certain individuals that are genetically susceptible to diabetic renal and extrarenal disease.
Vlassara
H
H
Picower Institute for Medical Research, Manhasset, NY 11030, USA.
D000818:Animals; D001161:Arteriosclerosis / Q000503:physiopathology*; D003920:Diabetes Mellitus / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000503:physiopathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017127:Glycation End Products, Advanced / Q000737:chemistry / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D011956:Receptors, Cell Surface
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D011956:Receptors, Cell Surface; C004479:pimagedine