Effect of gliclazide on monocyte-endothelium interactions in diabetes

Enhanced monocyte-endothelial cell interactions have been documented in dia betes. Because adherence of monocytes to the endothelium is one of the earl iest events in the development of atherosclerosis, its alteration may repre sent one of the mechanisms leading to accelerated atherosclerosis in diabet ic patients. Previous studies have suggested that lipoprotein oxidation and protein glycation may contribute to the increased monocyte binding to the diabetic vasculature. Based on the recent finding that gliclazide has free- radical scavenging activity, we examined the ex vivo and in vitro effects o f this drug on human monocyte binding to endothelial cells. Our results dem onstrate that short-term administration of gliclazide to patients with type 2 diabetes lowers the enhanced adhesion of diabetic monocytes observed bef ore gliclazide treatment (163+/-24% over control values, p<0.005) to levels similar to those observed in controls. They also show that gliclazide (10 mu g/ml) reduces in vitro by approximately 35% both oxidized low-density li poprotein (LDL)- and glycated albumin-induced monocyte adhesion to endothel ial cells. Based on these results, we next investigated the molecular mecha nisms responsible for the inhibitory effect of gliclazide on glycated album in-induced monocyte adhesion to endothelium. In glycated albumin-treated en dothelial cells, we observed induction of cell-associated expression of E-s electin (ELAM-1; 170+/-10% over control values, p<0.005), intercellular cel l adhesion molecule-1 (ICAM-1; 131+/-8% over control values, p<0.005) and v ascular cell adhesion molecule-1 (VCAM-1; 134+/-8% over control values, p<0 .005), augmentation in the levels of the transcripts of these molecules, an d an increase in the DNA binding of NF-kappa B in the promoters of these an tigens. Gliclazide markedly inhibited the induction of all these parameters . Because the oxidative stress-sensitive transcription factor NF-kappa B is implicated in endothelial cell activation, the observed inhibitory effect of gliclazide on NF-kappa B activation and glycated albumin-induced express ion of DNA binding activity for the NF-kappa B Site in the ELAM-1, ICAM-1 a nd VCAM-1 promoters seems to be due to its antioxidant properties. These re sults suggest that gliclazide, by its ability to reduce endothelial activat ion, may exert potential beneficial effects ih the prevention of atheroscle rosis associated with type 2 diabetes. (C) 2000 Elsevier Science Inc. All r ights reserved.