Resveratrol inhibits TNF-alpha-induced proliferation and matrix metalloproteinase expression in human vascular smooth muscle cells.
Resveratrol (RV), a polyphenolic substance found in grape skin, was suggested to play a role in preventing the development of atherosclerotic disease. Although RV has antiatherogenic effects on vascular smooth muscle cells (VSMC), the molecular mechanisms associated with tumor necrosis factor (TNF)-alpha-induced VSMC are unclear. The goal of this study was to determine the effect of RV on the modulation of cell proliferation, cell-cycle regulation, and matrix metalloproteinase (MMP)-9 expression in TNF-alpha-induced human VSMC. RV treatment inhibited DNA synthesis in cultured VSMC in the presence of TNF-alpha. These inhibitory effects were associated with reduced levels of extracellular signal-regulated kinase (ERK) 1/2 activity and G(1) cell-cycle arrest. Treatment with RV, which blocks the cell cycle in the G(1) phase, downregulated the expression of cyclins and cyclin-dependent kinases (CDKs) and upregulated the expression of p21/WAF1, a CDK inhibitor. RV did not upregulate p27. Moreover, RV increased the promoter activity of the p21/WAF1 gene. Immunoblot and deletion analysis of the p21/WAF1 promoter showed that RV induced the expression of p21/WAF1 and that this expression was independent of the p53 pathway. Furthermore, zymographic and immunoblot analyses showed that RV dose dependently suppressed the TNF-alpha-induced expression of MMP-9. This inhibition was characterized by the downregulation of MMP-9, which was transcriptionally regulated at the activator protein-1 (AP-1) and nuclear factor-kappaB (NF-kappaB) sites in the MMP-9 promoter. Collectively, these results suggest that RV inhibits cell proliferation, 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.
Lee
Beobyi
B
Department of Anatomy, College of Medicine, Konkuk University, Chungju City, Chungbuk 380-701, South Korea.
Moon
Sung-Kwon
SK
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D001011:Aorta; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects*; D002478:Cells, Cultured; D017930:Genes, Reporter; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D045726:Metalloproteases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000494:pharmacology*
D020533:Angiogenesis Inhibitors; D013267:Stilbenes; D014409:Tumor Necrosis Factor-alpha; D045726:Metalloproteases; D020780:Matrix Metalloproteinase 9; D000077185:Resveratrol