Enhanced cellular oxidant stress by the interaction of advanced glycation end products with their receptors/binding proteins.
Attack by reactive oxygen intermediates, common to many kinds of cell/tissue injury, has been implicated in the development of diabetic and other vascular diseases. Such oxygen-free radicals can be generated by advanced glycation end products (AGEs), which are nonenzymatically glycated and oxidized proteins. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGE (RAGE) and the lactoferrin-like polypeptide (LF-L), we tested the hypothesis that AGE ligands tethered to the complex of RAGE and LF-L could induce oxidant stress. AGE albumin or AGEs immunoisolated from diabetic plasma resulted in induction of endothelial cell (EC) oxidant stress, including the generation of thiobarbituric acid reactive substances (TBARS) and resulted in the activation of NF-kappa B, each of which was blocked by antibodies to AGE receptor polypeptides and by antioxidants. Infusion of AGE albumin into normal animals led to the appearance of malondialdehyde determinants in the vessel wall and increased TBARS in the tissues, activation of NF-kappa B, and induction of heme oxygenase mRNA. AGE-induced oxidant stress was inhibited by pretreatment of animals with either antibodies to the AGE receptor/binding proteins or antioxidants. These data indicate that interaction of AGEs with cellular targets, such as ECs, leads to oxidant stress resulting in changes in gene expression and other cellular properties, potentially contributing to the development of vascular lesions. Further studies will be required to dissect whether oxidant stress occurs on the cell surface or at an intracellular locus.
Yan
S D
SD
Department of Physiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Schmidt
A M
AM
Anderson
G M
GM
Zhang
J
J
Brett
J
J
Zou
Y S
YS
Pinsky
D
D
Stern
D
D
D000311:Adrenal Glands / Q000098:blood supply; D000328:Adult; D000818:Animals; D000906:Antibodies; D001483:Base Sequence; D001667:Binding, Competitive; D015152:Blotting, Northern; D002196:Capillaries; D002417:Cattle; D002478:Cells, Cultured; D002846:Chromatography, Affinity; D016384:Consensus Sequence; D003920:Diabetes Mellitus / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D004789:Enzyme Activation; D017127:Glycation End Products, Advanced / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*; D006419:Heme Oxygenase (Decyclizing) / Q000096:biosynthesis / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007700:Kinetics; D008315:Malondialdehyde / Q000032:analysis; D051379:Mice; D008833:Microcirculation / Q000166:cytology / Q000378:metabolism; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D015345:Oligonucleotide Probes / Q000378:metabolism / Q000494:pharmacology; D010100:Oxygen / Q000633:toxicity*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000187:drug effects / Q000378:metabolism*; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis
D000906:Antibodies; D017127:Glycation End Products, Advanced; D016328:NF-kappa B; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D017392:Thiobarbituric Acid Reactive Substances; D008315:Malondialdehyde; D006419:Heme Oxygenase (Decyclizing); D010100:Oxygen