The ascochlorin derivative, AS-6, inhibits TNF-α-induced adhesion molecule and chemokine expression in rat vascular smooth muscle cells

• Published in: Life sciences (1973) Vol. 80; no. 2; pp. 120 - 126
• Main Authors: Park, Keun-Gyu, Lee, Kyeong-Min, Chang, Young-Chae, Magae, Junji, Ando, Kunio, Kim, Kwon-Bae, Kim, Yoon-Nyun, Kim, Hye-Soon, Park, Joong-Yeol, Lee, Ki-Up, Lee, In-Kyu
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 14.12.2006
• Subjects: Adenoviridae - genetics; Adenovirus; Alkenes - chemistry; Animals; Aorta, Thoracic - cytology; Ascochlorin-6; Atherosclerosis; Blotting, Northern; Blotting, Western; Cells, Cultured; Chemokine CCL2 - metabolism; Chemokine CX3CL1; Chemokines, CX3C - biosynthesis; Chemokines, CX3C - genetics; CX3CL1; Gene Expression - drug effects; Genetic Vectors; Glycolates - pharmacology; Ligands; Male; MCP-1; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Muscle, Smooth, Vascular - cytology; NF-kappa B - metabolism; Phenols - chemistry; PPAR gamma - genetics; PPAR gamma - metabolism; PPARγ; Rats; Rats, Sprague-Dawley; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Transfection; Tumor Necrosis Factor-alpha - pharmacology; Vascular Cell Adhesion Molecule-1 - biosynthesis; Vascular Cell Adhesion Molecule-1 - genetics; Vascular smooth muscle cell; VCAM-1; MCP-1; VCAM-1; Ascochlorin-6; Atherosclerosis; Vascular smooth muscle cell; CX3CL1; PPARγ
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2006.08.030

Vascular inflammation induced by the proinflammatory cytokine/NF-κB pathway is one of the key mechanisms in the development of atherosclerosis. Peroxisome proliferators-activated receptor-γ (PPARγ) plays an important role in the prevention of arterial inflammation and formation of atherogenesis. Herein we examine the effects of a newly identified synthetic PPARγ ligand, ascochlorin-6 (AS-6), on TNF-α-stimulated NF-κB activity and inflammatory molecule expression in vascular smooth muscle cells (VSMCs). AS-6 successfully inhibited TNF-α-stimulated NF-κB 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-κB]×4 luciferase reporter construct showed that AS-6 inhibition of TNF-α-stimulated NF-κB activation was PPARγ-dependent. The effects of AS-6 on TNF-α-stimulated VCAM-1 and CX3CL1 expression were abolished in cells transfected with an adenovirus expressing dominant-negative PPARγ and in cells treated with a PPARγ specific inhibitor, GW9662, confirming again that the anti-inflammatory effect of AS-6 was PPARγ-dependent. The inhibitory effects of AS-6 on TNF-α-stimulated inflammatory gene expression and NF-κB activation were more potent than those of rosiglitazone and pioglitazone. This study shows that AS-6 reduces the inflammatory response to TNF-α in VSMCs. The data suggest the possibility that AS-6 can be used to prevent the development and progression of atherosclerosis.