This Article Full Text Full Text (PDF) All Versions of this Article: 105/20/2404    most recent 01.CIR.0000016349.36385.FBv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Iijima, K. Articles by Ouchi, Y. Search for Related Content PubMed PubMed Citation Articles by Iijima, K. Articles by Ouchi, Y. Related Collections Mechanism of atherosclerosis/growth factors Cell signalling/signal transduction

(Circulation. 2002;105:2404.)
© 2002 American Heart Association, Inc.

Basic Science Reports

Red Wine Polyphenols Inhibit Vascular Smooth Muscle Cell Migration Through Two Distinct Signaling Pathways

Katsuya Iijima, MD, PhD; Masao Yoshizumi, MD, PhD; Masayoshi Hashimoto, MD, PhD; Masahiro Akishita, MD, PhD; Koichi Kozaki, MD, PhD; Junya Ako, MD; Tokumitsu Watanabe, MD; Yumiko Ohike, MD; Bokyung Son, MD; Jing Yu, MD; Koichi Nakahara, PhD; Yasuyoshi Ouchi, MD, PhD

From the Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, and Institute for Fundamental Research (K.N.), Suntory Research Center, Suntory Ltd, Osaka, Japan.

Correspondence to Yasuyoshi Ouchi, MD, PhD, Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail youchi-tky{at}umin.ac.jp

Background— Red wine polyphenols (RWPs) have been shown to have an antiatherogenic activity mainly through antioxidative effects on LDL oxidation. Although vascular smooth muscle cell (SMC) migration is critical to atherosclerosis formation, the effect of RWPs on SMC migration has not been elucidated. In this study, we investigated whether RWPs could affect the migration of cultured SMCs stimulated by growth factors.

Methods and Results— RWP concentration dependently inhibited platelet-derived growth factor (PDGF)-BB–induced and serum-induced SMC migration in wounding assay and Boyden chamber assay. However, these inhibitory effects of RWPs were not seen in serum-stimulated vascular endothelial cell migration in either assay. Moreover, specific inhibitors of phosphatidylinositol-3' kinase (PI3K) and p38 mitogen-activated protein kinase (p38^MAPK), but not of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2), reduced PDGF-BB–induced SMC migration. To elucidate the signaling mechanism underlying the RWP effects, we investigated the effects of RWPs on the activity of PI3K and the phosphorylation of MAPK pathways in PDGF-BB–stimulated SMCs. RWPs inhibited the PI3K activity and p38^MAPK phosphorylation, but not ERK1/2 phosphorylation, in a concentration-dependent manner. Moreover, the phosphorylation of MKK3/6, an upstream kinase of p38^MAPK, was also inhibited by RWP treatment in a concentration-dependent manner, suggesting that the inhibitory effect of RWPs on the p38^MAPK pathway works upstream of MKK3/6. The concentration-effect relationship of RWPs necessary for the inhibition of PI3K and p38^MAPK pathways was similar to that of cell migration assays.

Conclusions— RWPs inhibit the SMC migration through the inhibition of 2 distinct signaling pathways and thus exert antiatherogenic actions.

Key Words: muscle, smooth • endothelium • atherosclerosis

This article has been cited by other articles:

				J. Lefevre, S.-E. Michaud, P. Haddad, S. Dussault, C. Menard, J. Groleau, J. Turgeon, and A. Rivard Moderate consumption of red wine (cabernet sauvignon) improves ischemia-induced neovascularization in ApoE-deficient mice: effect on endothelial progenitor cells and nitric oxide FASEB J, December 1, 2007; 21(14): 3845 - 3852. [Abstract] [Full Text] [PDF]

				C. Baron-Menguy, A. Bocquet, A.-L. Guihot, D. Chappard, M.-J. Amiot, R. Andriantsitohaina, L. Loufrani, and D. Henrion Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic FASEB J, November 1, 2007; 21(13): 3511 - 3521. [Abstract] [Full Text] [PDF]

				C.-K. Lee, H. M. Lee, H. J. Kim, H.-J. Park, K.-J. Won, H. Y. Roh, W. S. Choi, B. H. Jeon, T.-K. Park, and B. Kim Syk contributes to PDGF-BB-mediated migration of rat aortic smooth muscle cells via MAPK pathways Cardiovasc Res, April 1, 2007; 74(1): 159 - 168. [Abstract] [Full Text] [PDF]

				E. Anselm, M. Chataigneau, M. Ndiaye, T. Chataigneau, and V. B. Schini-Kerth Grape juice causes endothelium-dependent relaxation via a redox-sensitive Src- and Akt-dependent activation of eNOS Cardiovasc Res, January 15, 2007; 73(2): 404 - 413. [Abstract] [Full Text] [PDF]

				S. Li, H. Tanaka, H. H. Wang, S. Yoshiyama, H. Kumagai, A. Nakamura, D. L. Brown, S. E. Thatcher, G. L. Wright, and K. Kohama Intracellular signal transduction for migration and actin remodeling in vascular smooth muscle cells after sphingosylphosphorylcholine stimulation Am J Physiol Heart Circ Physiol, September 1, 2006; 291(3): H1262 - H1272. [Abstract] [Full Text] [PDF]

				S. Zhuang, Y. Yan, J. Han, and R. G. Schnellmann p38 Kinase-mediated Transactivation of the Epidermal Growth Factor Receptor Is Required for Dedifferentiation of Renal Epithelial Cells after Oxidant Injury J. Biol. Chem., June 3, 2005; 280(22): 21036 - 21042. [Abstract] [Full Text] [PDF]

				P. E. Szmitko and S. Verma Antiatherogenic potential of red wine: clinician update Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2023 - H2030. [Abstract] [Full Text] [PDF]

				K. J. Mukamal, A. Ascherio, M. A. Mittleman, K. M. Conigrave, C. A. Camargo Jr, I. Kawachi, M. J. Stampfer, W. C. Willett, and E. B. Rimm Alcohol and Risk for Ischemic Stroke in Men: The Role of Drinking Patterns and Usual Beverage Ann Intern Med, January 4, 2005; 142(1): 11 - 19. [Abstract] [Full Text] [PDF]

				H. Yamaguchi, M. Igarashi, A. Hirata, N. Sugae, H. Tsuchiya, Y. Jimbu, M. Tominaga, and T. Kato Altered PDGF-BB-Induced p38 MAP Kinase Activation in Diabetic Vascular Smooth Muscle Cells: Roles of Protein Kinase C-{delta} Arterioscler. Thromb. Vasc. Biol., November 1, 2004; 24(11): 2095 - 2101. [Abstract] [Full Text] [PDF]

				M. Dell'Agli, A. Busciala, and E. Bosisio Vascular effects of wine polyphenols Cardiovasc Res, September 1, 2004; 63(4): 593 - 602. [Abstract] [Full Text] [PDF]

				J.-S. Choi, Y.-J. Choi, S.-H. Park, J.-S. Kang, and Y.-H. Kang Flavones Mitigate Tumor Necrosis Factor-{alpha}-Induced Adhesion Molecule Upregulation in Cultured Human Endothelial Cells: Role of Nuclear Factor-{kappa}B J. Nutr., May 1, 2004; 134(5): 1013 - 1019. [Abstract] [Full Text] [PDF]

				M. Kyaw, M. Yoshizumi, K. Tsuchiya, S. Kagami, Y. Izawa, Y. Fujita, N. Ali, Y. Kanematsu, K. Toida, K. Ishimura, et al. Src and Cas Are Essentially but Differentially Involved in Angiotensin II-Stimulated Migration of Vascular Smooth Muscle Cells via Extracellular Signal-Regulated Kinase 1/2 and c-Jun NH2-Terminal Kinase Activation Mol. Pharmacol., April 1, 2004; 65(4): 832 - 841. [Abstract] [Full Text]

				G.-D. Sharma, J. He, and H. E. P. Bazan p38 and ERK1/2 Coordinate Cellular Migration and Proliferation in Epithelial Wound Healing: EVIDENCE OF CROSS-TALK ACTIVATION BETWEEN MAP KINASE CASCADES J. Biol. Chem., June 6, 2003; 278(24): 21989 - 21997. [Abstract] [Full Text] [PDF]

				M.-H. Oak, M. Chataigneau, T. Keravis, T. Chataigneau, A. Beretz, R. Andriantsitohaina, J.-C. Stoclet, S.-J. Chang, and V. B. Schini-Kerth Red Wine Polyphenolic Compounds Inhibit Vascular Endothelial Growth Factor Expression in Vascular Smooth Muscle Cells by Preventing the Activation of the p38 Mitogen-Activated Protein Kinase Pathway Arterioscler. Thromb. Vasc. Biol., June 1, 2003; 23(6): 1001 - 1007. [Abstract] [Full Text] [PDF]

				M. A. Carluccio, L. Siculella, M. A. Ancora, M. Massaro, E. Scoditti, C. Storelli, F. Visioli, A. Distante, and R. De Caterina Olive Oil and Red Wine Antioxidant Polyphenols Inhibit Endothelial Activation: Antiatherogenic Properties of Mediterranean Diet Phytochemicals Arterioscler. Thromb. Vasc. Biol., April 1, 2003; 23(4): 622 - 629. [Abstract] [Full Text] [PDF]

				M. A. Albert, R. J. Glynn, and P. M Ridker Alcohol Consumption and Plasma Concentration of C-Reactive Protein Circulation, January 28, 2003; 107(3): 443 - 447. [Abstract] [Full Text] [PDF]