A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-α-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells

Thiazoli dinedi ones (TZDs) are anti-diabetic agents that enhance insulin sensitivity through activating peroxisome proliferator-activated receptor (PPAR) gamma. Besides their glucose-lowering effects, TZDs are shown to exhibit anti - inflammatory properties in vascular cells, although their precise molecular mechanisms are unknown. In the present study, we examined the effects of a novel TZD MCC-555, which has unique characteristics of ability to activate not only PPAR-gamma but also PPAR alpha and PPAR delta on vascular cell adhesion molecule-1 (VCAM- 1) expression in vascular endothelial cells (ECs). Human aortic ECs were treated with MCC-555, followed by stimulation with tumor necrosis factor (TNF)-alpha. Cell surface VCAM-1 protein expression and human monocytoid U937 cell adhesion to these cells were determined. MCC-555 efficiently inhibited TNF-alpha-stimulated VCAM-11 expression and U937 cell adhesion. Transient transfection of bovine aortic ECs with a VCAM-1 promoter construct revealed that MCC-555 inhibited TNF-alpha-induced VCAM-1 promoter activity. Electrophoretic mobility-shift assay demonstrated that MCC-555 reduced the amount of nuclear factor-kappa B (NF-kappa B) bound to its recognition site on the VCAM-1 promoter. The considered PPAR delta activator GW501516 and the considered PPARa activator fenofibrate also inhibited TNF-alpha-induced VCAM-1 expression, whereas pioglitazone and rosiglitazone did not. These results indicate that MCC-555 is a strong TZD agent to inhibit the cytokine-induced VCAM-1 expression in vascular ECs. This effect is exerted probably through activation of PPAR alpha and/or PPAR delta, rather than PPAR gamma, mediating down-regulation of NF-kappa B activity. (c) 2005 Elsevier Ireland Ltd. All rights reserved.