title: The ascochlorin derivative, AS-6, inhibits TNF-alpha-induced adhesion molecule and chemokine expression in rat vascular smooth muscle cells.
abstract: Vascular inflammation induced by the proinflammatory cytokine/NF-kappaB pathway is one of the key mechanisms in the development of atherosclerosis. Peroxisome proliferators-activated receptor-gamma (PPARgamma) plays an important role in the prevention of arterial inflammation and formation of atherogenesis. Herein we examine the effects of a newly identified synthetic PPARgamma ligand, ascochlorin-6 (AS-6), on TNF-alpha-stimulated NF-kappaB activity and inflammatory molecule expression in vascular smooth muscle cells (VSMCs). AS-6 successfully inhibited TNF-alpha-stimulated NF-kappaB activity and inflammatory molecule expression, including vascular cell adhesion molecule-1 (VCAM-1), monocyte chemotactic protein-1 (MCP-1), and fractalkine (CX3CL1). Transient transfection with an [NF-kappaB]x4 luciferase reporter construct showed that AS-6 inhibition of TNF-alpha-stimulated NF-kappaB activation was PPARgamma-dependent. The effects of AS-6 on TNF-alpha-stimulated VCAM-1 and CX3CL1 expression were abolished in cells transfected with an adenovirus expressing dominant-negative PPARgamma and in cells treated with a PPARgamma specific inhibitor, GW9662, confirming again that the anti-inflammatory effect of AS-6 was PPARgamma-dependent. The inhibitory effects of AS-6 on TNF-alpha-stimulated inflammatory gene expression and NF-kappaB activation were more potent than those of rosiglitazone and pioglitazone. This study shows that AS-6 reduces the inflammatory response to TNF-alpha in VSMCs. The data suggest the possibility that AS-6 can be used to prevent the development and progression of atherosclerosis.
authors.affiliation: Department of Internal Medicine and Institute for Medical Science, Keimyung University School of Medicine, Daegu, South Korea.
authors.forename: Keun-Gyu
authors.initials: KG
authors.lastname: Park
authors.forename: Kyeong-Min
authors.initials: KM
authors.lastname: Lee
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.forename: Kunio
authors.initials: K
authors.lastname: Ando
authors.forename: Kwon-Bae
authors.initials: KB
authors.lastname: Kim
authors.forename: Yoon-Nyun
authors.initials: YN
authors.lastname: Kim
authors.forename: Hye-Soon
authors.initials: HS
authors.lastname: Kim
authors.forename: Joong-Yeol
authors.initials: JY
authors.lastname: Park
authors.forename: Ki-Up
authors.initials: KU
authors.lastname: Lee
authors.forename: In-Kyu
authors.initials: IK
authors.lastname: Lee
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000475:Alkenes / Q000737:chemistry*; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology; D015152:Blotting, Northern; D015153:Blotting, Western; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C / Q000096:biosynthesis* / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D005822:Genetic Vectors; D006016:Glycolates / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010636:Phenols / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000475:Alkenes; C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D054428:Chemokine CX3CL1; D020523:Chemokines, CX3C; C515540:Cx3cl1 protein, rat; D006016:Glycolates; D008024:Ligands; D008565:Membrane Proteins; D016328:NF-kappa B; D047495:PPAR gamma; D010636:Phenols; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C043832:4-O-carboxymethylascochlorin; C415745:ascochlorin