Non-enzymatic glycation of proteins is closely linked to oxidative processes. Attack by reactive oxygen species (ROS), 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 endproducts (AGEs), which are non-enzymatically glycated and oxidized proteins. The finding that advanced glycation endproducts are formed on hemoglobin suggests that glycated hemoglobin (GHb) is a precursor for advanced glycation endproducts formation. Since cellular interactions of AGEs are mediated by specific cellular binding proteins, receptor for AGEs (RAGE), we tested the hypothesis that advanced glycation endproducts modified hemoglobin (AGEs-Hb) bound to cellular surfaces induce oxidant stress.

Consistent with a role for binding of AGEs-Hb to mononuclear phagocytes for their induction of monocytes oxidant stress, generation of TBARS was blocked by either anti-RAGE IgG or anti-CD163 IgG, both of which independently prevented binding of AGEs-Hb to the surface of monocytes. Pretreatment of monocytes with antioxidants, probucol, or N-acetylcysteine also blocked advanced glycation endproducts modified hemoglobin-induced generation of TBARS, indicative of oxidant stress underlying TBARS formation. AGEs-Hb-induced monocytes oxidant stress was largely blocked on addition of either superoxide dismutase, catalase, or glutathione peroxidase to the medium, suggesting the involvement of multiple species of oxygen-free radicals, including superoxide and hydrogen peroxide.

Our data showing that advanced glycation endproducts modified hemoglobin-mediated production of ROS can generate an oxidant stress in target monocytes via interaction with specific AGEs-Hb binding sites, RAGE and CD163. This result is in favor of the possibility that our data could be explained by a more specific yet unidentified mechanism. Furthermore, the studies in which superoxide dismutase, catalase, and glutathione peroxidase (which would not be expected to gain access to the cytosol) blocked induction of oxidant stress suggest that AGEs-Hb-mediated generation of ROS occurs at the cell surface or in a pool of endocytosed ligand to which the added oxygen radical scavengers had access.

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