These results provide new insight into the cardioprotective action of estrogen as well as a paradigm of the response-to-injury hypothesis.

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. Key Words: red wine Ⅲ polyphenol Ⅲ atherosclerosis Ⅲ smooth muscle cells T he French population has lower morbidity and mortality from coronary heart disease (CHD) than other Western populations despite their high-fat and high-cholesterol diet. 1,2 Recently, it has been shown that this paradoxical finding, the "French paradox," may be attributed to regular consumption of red wine and that the unique antiatherogenic effects of red wine reside in the action of polyphenols. 2 LDL oxidation is known to be one of the initial events in atherogenesis, 3,4 and the antioxidative effects of red wine polyphenols, which have been shown in vitro 5 and in vivo, 6 may be involved in the mechanism of the French paradox. 7 Other aspects of atherogenesis are the dedifferentiation of vascular smooth muscle cells (VSMCs), their migration into the intima, and excessive proliferation of VSMCs in the neointima. 8 Although VSMC proliferation plays an important role in the pathogenesis of atherosclerotic lesions, the effects of red wine polyphenols on VSMC proliferation in atherosclerotic lesions have not been elucidated.Cyclin A is important in the G 1 /S transition and in the S and G 2 /M phases of the cell cycle and has a critical role in DNA replication. 9 The cyclin A promoter contains activating transcription factor (ATF) or cAMP-responsive element (CRE), which are bound by cAMP-responsive elementbinding protein (CREB) and ATF-1 by heterodimer formation. 10 The heterodimeric binding to the cyclin A ATF site is strongly ...

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