title: A novel thiazolidinedione MCC-555 down-regulates tumor necrosis factor-alpha-induced expression of vascular cell adhesion molecule-1 in vascular endothelial cells.
abstract: Thiazolidinediones (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 PPARgamma but also PPARalpha and PPARdelta 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-11expression 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-kappaB (NF-kappaB) bound to its recognition site on the VCAM-1 promoter. The considered PPARdelta activator GW501516 and the considered PPARalpha 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 PPARalpha and/or PPARdelta, rather than PPARgamma, mediating down-regulation of NF-kappaB activity.
authors.affiliation: Department of Molecular Medicine, Osaka University Graduate School of Medicine (C-4), 2-2 Yamada-oka, Suita-city, Osaka 565-0871, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Kurebayashi
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.forename: Shinichi
authors.initials: S
authors.lastname: Ishii
authors.forename: Muneshige
authors.initials: M
authors.lastname: Shiraishi
authors.forename: Haruhiko
authors.initials: H
authors.lastname: Kouhara
authors.forename: Soji
authors.initials: S
authors.lastname: Kasayama
mesh_terms: D001011:Aorta / Q000166:cytology; D002448:Cell Adhesion / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007333:Insulin Resistance; D016328:NF-kappa B / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D007004:Hypoglycemic Agents; D016328:NF-kappa B; D047493:PPAR alpha; D047495:PPAR gamma; D013844:Thiazoles; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C115174:netoglitazone