title: Epigallocatechin-3-gallate causes the p21/WAF1-mediated G(1)-phase arrest of cell cycle and inhibits matrix metalloproteinase-9 expression in TNF-alpha-induced vascular smooth muscle cells.
abstract: It has been suggested that epigallocatechin-3-gallate (EGCG), a major catechin found in green tea, plays a role in preventing the progression of atherosclerosis. Although EGCG has anti-atherogenic effects on vascular smooth muscle cells (VSMC), the molecular mechanisms associated with TNF-alpha-induced VSMC are not known with certainty. To determine whether EGCG has the capacity to modulate VSMC responses, cell cycle regulation and MMP-9 expression were examined in TNF-alpha-induced VSMC. Treatment with EGCG, which blocks the cell cycle in the G(1) phase, induced a down-regulation of cyclins and CDKs and an up-regulation in the expression of p21/WAF1, a CDK inhibitor, whereas the up-regulation of p27 by EGCG was not observed. Moreover, treatment with EGCG markedly increased the promoter activity of the p21/WAF1 gene. Immunoblot and deletion analysis results for the p21/WAF1 promoter showed that EGCG induced the expression of p21/WAF1 independent of the p53 pathway. Zymographic and immunoblot analyses showed that EGCG suppressed TNF-alpha-induced MMP-9 expression in a dose-dependent manner. Further experiments demonstrated that EGCG reduced the transcriptional activity of activator protein-1 (AP-1) and nuclear factor kappaB (NF-kappaB), two important nuclear transcription factors that are involved in MMP-9 expression. Collectively, these results suggest that EGCG inhibits G(1) to S-phase cell cycle progress and MMP-9 expression through the transcription factors NF-kappaB and AP-1 in TNF-alpha-induced VSMC.
authors.affiliation: Department of Biochemistry and Molecular Biology, Dongguk University COM, Kyungju City, Kyungbuk 780-714, Republic of Korea.
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Sung-Kwon
authors.initials: SK
authors.lastname: Moon
mesh_terms: D001161:Arteriosclerosis / Q000188:drug therapy / Q000378:metabolism; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D016193:G1 Phase / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011480:Protease Inhibitors / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D011480:Protease Inhibitors; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002392:Catechin; C045651:epigallocatechin gallate; D020780:Matrix Metalloproteinase 9