Resveratrol Inhibits TNF-[alpha]-Induced Proliferation and Matrix Metalloproteinase Expression in Human Vascular Smooth Muscle Cells
2005
Lee, Beobyi | Moon, Sung-Kwon
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 G₁ cell-cycle arrest. Treatment with RV, which blocks the cell cycle in the G₁ 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-[kappa]B (NF-[kappa]B) sites in the MMP-9 promoter. Collectively, these results suggest that RV inhibits cell proliferation, G₁ to S phase cell-cycle progress, and MMP-9 expression through the transcription factors NF-[kappa]B and AP-1 in TNF-[alpha]-induced VSMC.
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