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. AGEs induce a pro-oxidant stress in vascular cells, leading to increased NF-kB activity and monocyte chemoattractant protein-1 (MCP-1), both of which have been implicated in vascular lesion development. AGEs affect cellular gene expression, in part, by engaging certain cell surface receptors. One of these is known as RAGE (Receptor for AGEs). It is a member of the immunoglobulin superfamily of cell surface receptors. We have cloned RAGE from rat intimal vascular smooth muscle cells and constructed epitope-tagged wild type and mutant receptors and shown that overexpression of wild type receptor leads to increased NF-kB expression in some but not all cells tested. Signaling from the receptor results in increased Erk and p38 MAPK activities, both of which are required for Ik-Balpha degradation and the activitation of NF-kB and NF-kB-dependent gene expression. 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 and a previously identified leucine rich repeat (LRR) protein of unknown function known as p37NB. P37NB has a similar distribution of expression as RAGE. Overexpression of p37NB leads to increased cellular ras activity and NF-kB 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.