Effect of red wine polyphenols on vascular smooth muscle cell function--molecular mechanism of the 'French paradox'.
Red wine polyphenols (RWP) have been shown to have an anti-atherogenic activity mainly through anti-oxidative effects on low-density lipoprotein (LDL) oxidation. Though proliferation of vascular smooth muscle cells (VSMC) is critical to atherosclerosis formation, the effect of RWP on VSMC proliferation has not been elucidated. In this study, we investigated whether RWP, which extracted from red wine using column chromatography, could affect the 10% serum-stimulated VSMC proliferation. Treatment with RWP showed a potent inhibitory effect on the proliferation and DNA syntheses is in cultured rat VSMC. In contrast, the inhibitory effect of RWP on the proliferation of bovine vascular endothelial cells (EC) was only observed at much higher doses. Moreover, RWP significantly inhibited the proliferation and DNA synthesis of human VSMC but no human vascular EC in a dose-dependent manner. To elucidate the molecular mechanisms of these anti-proliferative effects of RWP on VSMC, but not on vascular EC, we investigated the effects of RWP on the cell cycle regulation. RWP downregulated the expression and promoter activity of cyclin A gene, one of cell cycle regulators. In addition, RWP inhibited the binding of nuclear proteins to the activating transcription factor (ATF) site in the cyclin A promoter, and downregulated the expression of transcription factors, cyclic AMP-responsive element binding protein (CREB) and ATF-1. In conclusion, these results demonstrate one possible finding that the anti-proliferative effect of RWP on VSMC may be associated with the downregulation of cyclin A gene expression through the inhibition of transcription factor expression.
Iijima
Katsuya
K
Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Yoshizumi
Masao
M
Ouchi
Yasuyoshi
Y
D051697:Activating Transcription Factor 1; D000818:Animals; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D019925:Cyclin A / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins; D005419:Flavonoids; D015870:Gene Expression / Q000187:drug effects*; D006131:Growth Inhibitors / Q000494:pharmacology*; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D010636:Phenols / Q000494:pharmacology*; D011108:Polymers / Q000494:pharmacology*; D059808:Polyphenols; D011485:Protein Binding; D051381:Rats; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects; D014920:Wine
D051697:Activating Transcription Factor 1; D017362:Cyclic AMP Response Element-Binding Protein; D019925:Cyclin A; D004268:DNA-Binding Proteins; D005419:Flavonoids; D006131:Growth Inhibitors; D010636:Phenols; D011108:Polymers; D059808:Polyphenols; D014157:Transcription Factors