Red wine polyphenols inhibit proliferation of vascular smooth muscle cellsand downregulate expression of cyclin A gene

Background-Red wine polyphenols have been shown to contribute to the "Frenc h 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 pr oliferation have not been elucidated. Methods and Results-We extracted the total polyphenolic fraction from red w ine (RW-PF) by column chromatography. Treatment with RW-PF showed a potent inhibitory effect on the proliferation and DNA synthesis of cultured rat ao rtic smooth muscle cells (RASMCs). In contrast, the inhibitory effect of RW -PF on the proliferation of bovine carotid endothelial cells was observed o nly at much higher concentrations. To elucidate the molecular mechanisms of this antiproliferative effect of RW-PF on RASMCs, we investigated the effe cts of RW-PF on cell cycle regulation. RW-PF downregulated the expression o f cyclin A mRNA and cyclin A promoter activity. In addition, RW-PF decrease d the binding of nuclear proteins to the activating transcription factor (A TF) site in the cyclin A promoter and downregulated the mRNA levels of tran scription 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 polyp henols on RASMCs through the inhibition of transcription factor expression.