Red wine polyphenols inhibit proliferation of vascular smooth muscle cells and downregulate expression of cyclin A gene.

BACKGROUND Red wine polyphenols have been shown to contribute to the "French paradox" phenomenon, which consists of lower morbidity and mortality from coronary heart disease in the French population. Although vascular smooth muscle cell (VSMC) proliferation plays an important role in the progression of atherosclerotic lesions, the effects of red wine polyphenols on VSMC proliferation have not been elucidated. METHODS AND RESULTS We extracted the total polyphenolic fraction from red wine (RW-PF) by column chromatography. Treatment with RW-PF showed a potent inhibitory effect on the proliferation and DNA synthesis of cultured rat aortic smooth muscle cells (RASMCs). In contrast, the inhibitory effect of RW-PF on the proliferation of bovine carotid endothelial cells was observed only at much higher concentrations. To elucidate the molecular mechanisms of this antiproliferative effect of RW-PF on RASMCs, we investigated the effects of RW-PF on cell cycle regulation. RW-PF downregulated the expression of cyclin A mRNA and cyclin A promoter activity. In addition, RW-PF decreased the binding of nuclear proteins to the activating transcription factor (ATF) site in the cyclin A promoter and downregulated the mRNA levels of transcription factors, cAMP-responsive element-binding protein (CREB), and ATF-1. CONCLUSIONS These results suggest that the downregulation of cyclin A gene expression may contribute to the antiproliferative effect of red wine polyphenols on RASMCs through the inhibition of transcription factor expression.