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

Publisher: Elsevier Country of Publication: Netherlands NLM ID: 0375521 Publication Model: Print-Electronic Cited Medium: Print ISSN: 0024-3205 (Print) Linking ISSN: 00243205 NLM ISO Abbreviation: Life Sci Subsets: MEDLINE

Publication: <2008->: Amsterdam : Elsevier
Original Publication: Oxford; Elmsford, N. Y. [etc.] Pergamon Press.

Alkenes/*chemistry ; Chemokines, CX3C/*biosynthesis ; Glycolates/*pharmacology ; Membrane Proteins/*biosynthesis ; Muscle, Smooth, Vascular/*cytology ; PPAR gamma/*metabolism ; Phenols/*chemistry ; Tumor Necrosis Factor-alpha/*pharmacology ; Vascular Cell Adhesion Molecule-1/*biosynthesis; Adenoviridae/genetics ; Animals ; Aorta, Thoracic/cytology ; Blotting, Northern ; Blotting, Western ; Cells, Cultured ; Chemokine CCL2/metabolism ; Chemokine CX3CL1 ; Chemokines, CX3C/genetics ; Gene Expression/drug effects ; Genetic Vectors ; Ligands ; Male ; Membrane Proteins/genetics ; NF-kappa B/metabolism ; PPAR gamma/genetics ; Rats ; Rats, Sprague-Dawley ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Transfection ; Vascular Cell Adhesion Molecule-1/genetics

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.

0 (Alkenes)
0 (Ccl2 protein, rat)
0 (Chemokine CCL2)
0 (Chemokine CX3CL1)
0 (Chemokines, CX3C)
0 (Cx3cl1 protein, rat)
0 (Glycolates)
0 (Ligands)
0 (Membrane Proteins)
0 (NF-kappa B)
0 (PPAR gamma)
0 (Phenols)
0 (Recombinant Proteins)
0 (Tumor Necrosis Factor-alpha)
0 (Vascular Cell Adhesion Molecule-1)
I1BK0ZE06X (4-O-carboxymethylascochlorin)
PEZ8F05ODV (ascochlorin)

Date Created: 20060923 Date Completed: 20070206 Latest Revision: 20171116

20231215

10.1016/j.lfs.2006.08.030

16989870