Monocyte adhesion in diabetic angiopathy: effects of free-radical scavenging.
Increased interaction of monocytes with vascular cells is linked to the development and progression of atherosclerosis in patients with diabetes. One major determinant of increased monocyte binding to vascular cells could be oxidative stress. Given the free-radical scavenging properties of gliclazide, we evaluated the ex vivo and in vitro effects of this drug on human monocyte binding to endothelial cells and smooth muscle cells (SMCs). Short-term administration of gliclazide to patients with type 2 diabetes decreases plasma lipid peroxides and lowers the enhanced adhesion of diabetic monocytes to cultured endothelial cells observed before gliclazide treatment. Gliclazide (10 microg/ml) also reduces oxidized low-density lipoprotein (oxLDL)- and advanced glycation end product (AGE)-induced monocyte adhesion to cultured endothelial cells. The suppressive effect of gliclazide on AGE-induced monocyte adhesion to endothelium involves a reduction of cell adhesion molecule mRNA and protein expression and an inhibition of NF-kappaB activation. Gliclazide also inhibits oxLDL-induced monocyte adhesion to cultured human aortic smooth muscle cells (HASMCs). Furthermore, treatment of HASMCs with gliclazide results in a marked decrease in oxLDL-induced monocyte chemoattractant protein-1 expression, both at the gene and protein levels. These results suggest that gliclazide, at concentrations in the therapeutic range (5-10 microg/ml), by its ability to decrease monocyte-vascular cell interactions could reduce monocyte accumulation in the atherosclerotic plaque and thereby contribute to attenuate the sustained inflammatory process that occurs in the vessel wall. These findings suggest that treatment of diabetic patients with gliclazide may prevent or retard the development of vascular disturbances associated with diabetes.
Renier
Geneviève
G
CHUM Research Centre, Metabolic Unit, Notre-Dame Hospital, 3rd floor, J.A. de Sève, Y-3622, 1560 Sherbrooke Street East, Quebec, H2L 4M1, Montreal, Canada. genevieve.renier@umontreal.ca
Mamputu
Jean Claude
JC
Desfaits
Anne Cécile
AC
Serri
Omar
O
D000368:Aged; D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000166:cytology; D002417:Cattle; D002448:Cell Adhesion / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D003925:Diabetic Angiopathies / Q000517:prevention & control; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects; D005260:Female; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005907:Gliclazide / Q000494:pharmacology* / Q000627:therapeutic use; D017127:Glycation End Products, Advanced / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects; D012709:Serum Albumin / Q000502:physiology
D016166:Free Radical Scavengers; D017127:Glycation End Products, Advanced; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D012709:Serum Albumin; D005907:Gliclazide