AGEs and their interaction with AGE-receptors in vascular disease and diabetes mellitus. I. The AGE concept.
OBJECTIVE
This is the first part of a bipartite review that summarizes the rising knowledge on the molecular mechanisms underlying the action of advanced glycation endproducts (AGEs) and their contribution to diabetic complications and vascular disease. While the first part presented here focusses on AGE formation, the second part will describe the AGE-protein/receptor interactions and their role in mediating AGE-dependent intracellular signalling.


RESULTS
Nonenzymatic glycation, in which reducing sugars are covalently attached to free amino groups and ultimately form AGEs, has been found to occur during normal aging and at accelerated rate in diabetes mellitus. Oxidation, accompanying glycation in vivo, further supports chemical modifications. AGE formation and protein crosslinking are irreversible processes that alter the structural and functional properties of proteins, lipid components and nucleic acids. AGE modifications do not only change the physicochemical properties of the afflicted molecules, but also induce cellular signalling, activation of transcription factors and subsequent gene expression in vitro and in vivo.


CONCLUSIONS
AGEs elicit a wide range of cell-mediated responses that might contribute to the pathogenesis of diabetic complications, vascular and renal disease and Alzheimer's disease. Substances that inhibit AGE formation, reduce oxidative stress or destroy already formed crosslinks may limit the progression of disease and may offer new tools for therapeutic interventions in the therapy of AGEs mediated disease.
Bierhaus
A
A
Department of Medicine I, University of Heidelberg, Germany.
Hofmann
M A
MA
Ziegler
R
R
Nawroth
P P
PP
D003920:Diabetes Mellitus / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006801:Humans; D015227:Lipid Peroxidation; D015416:Maillard Reaction; D014652:Vascular Diseases / Q000378:metabolism*
D017127:Glycation End Products, Advanced; D005947:Glucose