ADVANCED GLYCATION ENDPRODUCTS, THEIR RECEPTORS, AND VASCULAR DISEASE

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SUMMARY OF WORK Advanced glycation endproducts of proteins (AGE) accumulate in the plasma and in tissues with advancing age and at an accelerated rate in diabetes. Our previous work has shown that AGEs induce a pro-oxidant stress in vascular cells, leading to increased monocyte chemoattractant protein-1(MCP-1) production and increased PDGF B chain activity, both of which have been implicated in vascular lesion development. Our current research efforts are focussed on identifying the signaling pathways by which AGEs affect gene expression so that molecular strategies can be developed to block their effects. Our results indicate that signaling is initiated by the binding of AGEs to a unique receptor called RAGE (Receptor for AGEs). We have cloned RAGE from rat intimal vascular smooth muscle cells and constructed epitope-tagged wild type and mutant receptors and shown that transfection of wild type receptor leads to increased MCP-1 RNA levels in response to AGEs. Mutant receptors in which the cytosolic tail has been removed, however, fail to signal increased MCP-1 production in response to AGE stimulation, and, in fact, block the ability of either endogenous or transfected wild type receptors to signal. Two hybrid screening in yeast have identified a number of proteins that interact with the cytosolic tail of RAGE. These include the adapter protein, shc, which has been implicated in receptor mediated activation of MAPKinase pathways, a previously identified protein of unknown function known as p37NB, and several enzymes associated with protein ubiquination, which have recently been shown by others to associate with other signaling receptors only in response to ligand activation. These observations demonstrate that the cytosolic tail of RAGE can engage intracellular proteins important in signal transduction that may be responsible for AGE-induced changes in gene expression.