Gliclazide decreases vascular smooth muscle cell dysfunction induced by cell-mediated oxidized low-density...

Accumulating evidence indicates that oxidative modification of low-density lipoprotein (LDL) plays an important role in vascular dysfunction associated with diabetes mellitus. The aim of the present study was to investigate the effect of gliclazide, a second-generation sulfonylurea with free-radical-scavenging activity, on human aortic smooth muscle cell (HASMC)-mediated LDL oxidation and HASMC dysfunction induced by oxidatively modified LDL. Incubation of HASMCs with native human LDL (100 microg/mL) in the presence of increasing concentrations of gliclazide (1 to 10 microg/mL) resulted in a dose-dependent decrease in HASMC-mediated LDL oxidation. Exposure of HASMCs to gliclazide (1 to 10 microg/mL) and native LDL (100 microg/mL) also led to a dose-dependent decrease in oxidized LDL-induced human monocyte adhesion to HASMCs. In addition, incubation of HASMCs with gliclazide dramatically reduced the ability of oxidized LDL to stimulate the proliferation of these cells. Finally, treatment of HASMCs with gliclazide resulted in a marked decrease in oxidatively modified LDL-induced monocyte chemoattractant protein (MCP)-1 and human heat shock protein 70 (hsp 70) expression, both at the gene and protein levels. These results show that gliclazide, at concentrations in the therapeutic range (5 to 10 microg/mL), is effective in vitro in reducing vascular smooth muscle cell (VSMC) dysfunction induced by oxidatively modified LDL. These observations suggest that administration of gliclazide to type 2 diabetic patients could form part of the strategy for the prevention and management of diabetic cardiovascular diseases.