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Biochemical and Molecular Actions of Nutrients

Resveratrol Inhibits TNF-–Induced Proliferation and Matrix Metalloproteinase Expression in Human Vascular Smooth Muscle Cells

Department of Anatomy, College of Medicine, Konkuk University, Chungju City, Chungbuk 380–701, South Korea and ^* Department of Food and Biotechnology, Chungju National University, Chungju, Chungbuk 380–702, South Korea

¹To whom correspondence should be addressed. E-mail: sumoon66{at}dreamwiz.com.

ABSTRACT

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)-–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-–induced human VSMC. RV treatment inhibited DNA synthesis in cultured VSMC in the presence of TNF-. 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-–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-B (NF-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-B and AP-1 in TNF-–induced VSMC.

KEY WORDS: • resveratrol • vascular smooth muscle cell • matrix metalloproteinase-9 • G₁ cell-cycle arrest