title: Inhibitory effect of esculetin on migration, invasion and matrix metalloproteinase-9 expression in TNF-α-induced vascular smooth muscle cells.
abstract: Esculetin, a potent non-competitive inhibitor of lipoxygenase, has been shown to inhibit vascular smooth muscle cell (VSMC) proliferation. However, the effect of esculetin on the matrix metalloproteinase-9 (MMP-9) regulation responsible for cell migration and invasion has not been previously investigated. The results of the present study showed the esculetin (12.5-25 µg/ml) induced the inhibition of migration and invasion in tumor necrosis factor-α (TNF-α)-treated VSMC, as demonstrated by a matrigel invasion assay and wound healing analysis. However, esculetin did not affect cell viability in TNF-α-treated VSMC under 0-25 µg/ml concentration conditions. In addition, both zymographic and immunoblot experiments showed that esculetin suppressed the TNF-α-induced expression of MMP-9 in VSMC in a dose-dependent manner. Furthermore, the treatment of cells with esculetin decreased the activity of the TNF-α-induced MMP-9 promoter, which was driven by a luciferase reporter. Finally, esculetin reduced the binding activities of nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), which are cis-elements present in the promoter of the MMP-9 gene, in TNF-α-treated VSMC. Taken together, these results demonstrated that esculetin decreased the migration and invasion of cells by suppressing MMP-9 expression, which subsequently reduced the binding activities of NF-κB and AP-1 in TNF-α-treated VSMC. These novel findings provide basic information for effective therapeutic treatment with esculetin for atherosclerotic disease.
authors.affiliation: Department of Food and Biotechnology, Chungju National University, Chungju, Chungbuk 380-702, P.R. China.
authors.forename: Se-Jung
authors.initials: SJ
authors.lastname: Lee
authors.forename: Ung-Soo
authors.initials: US
authors.lastname: Lee
authors.forename: Wun-Jae
authors.initials: WJ
authors.lastname: Kim
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects*; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014468:Umbelliferones / Q000494:pharmacology*
chemical_list: D016328:NF-kappa B; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014468:Umbelliferones; D020780:Matrix Metalloproteinase 9; C007628:esculetin