title: The oral anti-diabetic agent, gliclazide, inhibits oxidized LDL-mediated LOX-1 expression, metalloproteinase-9 secretion and apoptosis in human aortic endothelial cells.
abstract: The mechanisms linking diabetes to plaque rupture and thrombotic occlusion remain largely speculative, yet matrix metalloproteinases (MMP) and endothelial apoptosis may represent central elements. Binding of oxidized low-density lipoprotein (oxLDL) to endothelial lectin-like oxidized LDL receptor-1 (LOX-1) induces oxidative stress, MMP expression and apoptosis. In the present study, we examined the effect of gliclazide, a second generation sulfonylurea with antioxidant properties, on LOX-1 expression and LOX-1-mediated MMP-9 expression and apoptosis in oxLDL-treated human aortic endothelial cells (HAECs). Incubation of HAECs with oxLDL increased LOX-1 expression and enhanced MMP-9 production by these cells. Treatment with an anti-LOX-1 antibody or with antioxidants, including gliclazide, inhibited these effects. Induction of LOX-1 and LOX-1-mediated MMP-9 production involved endothelin-1 production and nuclear factor-kappaB activation. These biological parameters were inhibited by gliclazide and anti-LOX-1 antibody treatment. In HAECs, oxLDL induced apoptosis, an effect associated with reduced protein kinase B (PKB) activity. Anti-LOX-1 antibody, antioxidants including gliclazide, as well as caspase inhibitors prevented oxLDL-induced apoptosis. The anti-apoptotic effect of gliclazide was associated with an increase in PKB activity and a decrease in caspase-3 and -9 activities. These results demonstrate that gliclazide inhibits endothelial LOX-1 expression and prevents LOX-1-mediated proatherogenic effects associated with endothelial dysfunction and plaque rupture.
authors.affiliation: CHUM Research Centre, Notre-Dame Hospital, Department of Medicine, University of Montreal, Quebec, Canada.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.forename: Geneviève
authors.initials: G
authors.lastname: Renier
mesh_terms: D000284:Administration, Oral; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D061945:Caspase Inhibitors; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D019332:Endothelin-1 / Q000378:metabolism; D005907:Gliclazide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008077:Lipoproteins, LDL / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000378:metabolism*
chemical_list: D000975:Antioxidants; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D019332:Endothelin-1; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D016328:NF-kappa B; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020780:Matrix Metalloproteinase 9; D005907:Gliclazide