ENDOTHELIAL-CELL ADHESION MOLECULE AND PMNL RESPONSE TO INFLAMMATORY STIMULI AND AGE-MODIFIED FIBRONECTIN

Background Atherosclerotic vascular disease is the leading cause of de ath in patients with diabetes mellitus and end-stage renal disease. Ad vanced glycation end products (AGEs) are strongly suggested to be invo lved in the pathogenesis of atherosclerosis in these patients who also frequently experience infectious complications. We hypothesized that the interaction of AGEs and inflammatory mediators contributes to the up-regulation of endothelial cell activation. Methods. We investigated the effect of advanced glycated fibronectin in the presence or absenc e of inflammatory stimuli on the endothelial cell surface and mRNA exp ression of cell adhesion molecules. Furthermore, the influence of adva nced glycated fibronectin on the transendothelial migration pattern of polymorphonuclear cells was analyzed. Results. Exposure to advanced g lycated fibronectin together with inflammatory stimuli such as interle ukin (IL)-1 alpha, tumor necrosis factor-alpha (TNF-alpha) or lipopoly saccharide (LPS) led to a significant increase in the surface expressi on of the cell adhesion molecules E-selectin, ICAM-1, VCAM-1 and PECAM -1 on endothelial cells. Soluble AGEs in combination with advanced gly cated fibronectin significantly enhanced the endothelial cell surface expression of ICAM-1, VCAM-1 and PECAM-1, whereas this was not the cas e for E-selectin. At the transcriptional level short-time exposure of endothelial cells to advanced glycated fibronectin and inflammatory me diators resulted in an increased expression of E-selectin, ICAM-1 and VCAM-1 mRNA levels, whereas PECAM-1 repeatedly showed a significant de crease of gene transcript levels. An increase of mRNA levels was also observed for E-selectin, ICAM-1, VCAM-1 and PECAM-1 following incubati on with a combination of advanced glycated fibronectin and soluble adv anced glycation end-products. Furthermore, polymorphonuclear cells res ponded with a sevenfold increase in transendothelial migration followi ng exposure of endothelial cells to advanced glycated fibronectin and inflammatory mediators. Conclusions. These results suggest that the co mbination of matrix glycation and inflammation up-regulates the activa tion of the endothelial cell adhesion cascade, a mechanism that might contribute to the increased burden of atherosclerotic morbidity and mo rtality in patients suffering from diabetes mellitus or chronic renal failure.