ADVANCED GLYCATION ENDPRODUCTS INTERACTING WITH THEIR ENDOTHELIAL RECEPTOR INDUCE EXPRESSION OF VASCULAR CELL-ADHESION MOLECULE-1 (VCAM-1) IN CULTURED HUMAN ENDOTHELIAL-CELLS AND IN MICE - A POTENTIAL MECHANISM FOR THE ACCELERATED VASCULOPATHY OF DIABETES

Vascular cell adhesion molecule-1 (VCAM-1), an inducible cell-cell rec ognition protein on the endothelial cell surface (EC), has been associ ated with early stages of atherosclerosis. In view of the accelerated vascular disease observed in patients with diabetes, and the enhanced expression of VCAM-1 in diabetic rabbits, we examined whether irrevers ible advanced glycation endproducts (AGEs), could mediate VCAM-1 expre ssion by interacting with their endothelial cell receptor (receptor fo r AGE, RAGE), Exposure of cultured human ECs to AGEs induced expressio n of VCAM-1, increased adhesivity of the monolayer for Molt-4 cells, a nd was associated with increased levels of VCAM-1 transcripts, The inh ibitory effect of anti-RAGE IgG, a truncated form of the receptor (sol uble RAGE) or N-acetylcysteine on VCAM-1 expression indicated that AGE -RAGE-induced oxidant stress was central to VCAM-1 induction, Electrop horetic mobility shift assays on nuclear extracts from AGE-treated ECs showed induction of specific DNA binding activity for NF-LB in the VC AM-1 promoter, which was blocked by anti-RAGE IgG or N-acetylcysteine. Soluble VCAM-1 antigen was elevated in human diabetic plasma, These d ata are consistent with the hypothesis that AGE-RAGE interaction induc es expression of VCAM-1 which can prime diabetic vasculature for enhan ced interaction with circulating monocytes.