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

• Published in: Atherosclerosis 2005-09, Vol.182 (1), p.71-77
• Main Authors: Kurebayashi, Shogo, Xu, Xin, Ishii, Shinichi, Shiraishi, Muneshige, Kouhara, Haruhiko, Kasayama, Soji
• Format: Article
• Language: English
• Subjects: Adhesion molecules; Aorta - cytology; Atherosclerosis; Atherosclerosis (general aspects, experimental research); Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Cell Adhesion - drug effects; Down-Regulation - drug effects; Endothelium; Endothelium, Vascular - cytology; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Gene Expression - drug effects; Humans; Hypoglycemic Agents - pharmacology; Insulin Resistance; Medical sciences; Metabolic diseases; NF-kappa B - metabolism; Obesity; PPAR alpha - metabolism; PPAR gamma - metabolism; Promoter Regions, Genetic - physiology; Thiazoles - pharmacology; Thiazolidinediones; Tumor Necrosis Factor-alpha - pharmacology; U937 Cells; Vascular biology; Vascular Cell Adhesion Molecule-1 - genetics; Vascular Cell Adhesion Molecule-1 - metabolism
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/j.atherosclerosis.2005.02.004

Thiazolidinediones (TZDs) are anti-diabetic agents that enhance insulin sensitivity through activating peroxisome proliferator-activated receptor (PPAR) γ. 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 PPARγ but also PPARα and PPARδ 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)-α. Cell surface VCAM-1 protein expression and human monocytoid U937 cell adhesion to these cells were determined. MCC-555 efficiently inhibited TNF-α-stimulated VCAM-11expression and U937 cell adhesion. Transient transfection of bovine aortic ECs with a VCAM-1 promoter construct revealed that MCC-555 inhibited TNF-α-induced VCAM-1 promoter activity. Electrophoretic mobility-shift assay demonstrated that MCC-555 reduced the amount of nuclear factor-κB (NF-κB) bound to its recognition site on the VCAM-1 promoter. The considered PPARδ activator GW501516 and the considered PPARα activator fenofibrate also inhibited TNF-α-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 PPARα and/or PPARδ, rather than PPARγ, mediating down-regulation of NF-κB activity.