Download PDF
Planta Med 2012; 78(08): 772-778
DOI: 10.1055/s-0031-1298440
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Synergy Study of the Inhibitory Potential of Red Wine Polyphenols on Vascular Smooth Muscle Cell Proliferation

Elena Kurin
1   Department of Pharmacognosy, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
,
Atanas G. Atanasov
2   Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Oliver Donath
2   Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Elke H. Heiss
2   Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Verena M. Dirsch
2   Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Vienna, Austria
,
Milan Nagy
1   Department of Pharmacognosy, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia
› Author Affiliations
Further Information

Publication History

received 14 December 2011
revised 21 March 2012

accepted 22 March 2012

Publication Date:
12 April 2012 (online)

Also available at
    Permissions and Reprints

Abstract

Vascular smooth muscle cell (VSMC) proliferation contributes to the development of atherosclerosis. Red wine consumption due to the polyphenol content has been reported to counteract atherosclerosis progression possibly through inhibition of VSMC proliferation, among other mechanisms. In this study we investigate the antiproliferative activity of four wine polyphenols: resveratrol, quercetin, ethyl gallate, and (+)-catechin in rat aortic VSMC. All four polyphenols inhibited serum-induced VSMC proliferation when applied as a single treatment. To further address a potential synergistic action of the investigated polyphenols, the antiproliferative effect of different combinations in equimolar, as well as equipotent ratios were quantified. The IC50 values of single polyphenols regarding the inhibition of VSMC proliferation ranged from 49.58 µM to 86.06 µM. However, apparent inhibitory efficacy of each compound increased by a factor of 10.4 in the quadruple equipotent mixture, as calculated from the dose-reduction index. Thus, the effective IC50 values of each of the four mixture constituents ranged from 4.76 µM to 8.27 µM. The calculated combination index (CI, where CI <, =, or > 1 indicate synergy, additivity, or antagonism, respectively) values of equimolar combinations of the polyphenols indeed indicated mainly synergy (CI ranging from 0.24 ± 0.01 to 1.51 ± 0.13). Optimized equipotent mixture showed enhanced synergy (CI ranging from 0.18 ± 0.04 to 1.36 ± 0.26). In conclusion, we show for the first time that four major polyphenols from wine synergistically inhibit VSMC proliferation.

Key words

interaction analysis - synergy - vascular smooth muscle cell proliferation - wine polyphenols - resveratrol - quercetin - ethyl gallate - (+)-catechin

Supporting Information

 

  • References

  • 1 Rader DJ, Daugherty A. Translating molecular discoveries into new therapies for atherosclerosis. Nature 2008; 451: 904-913
    CrossrefPubMedGoogle Scholar
  • 2 Ivey ME, Osman N, Little PJ. Endothelin-1 signalling in vascular smooth muscle: pathways controlling cellular functions associated with atherosclerosis. Atherosclerosis 2008; 199: 237-247
    CrossrefPubMedGoogle Scholar
  • 3 Dzau VJ, Braun-Dullaeus RC, Sedding DG. Vascular proliferation and atherosclerosis: new perspectives and therapeutic strategies. Nat Med 2002; 11: 1249-1256
    PubMedGoogle Scholar
  • 4 González-Gallego J, García-Mediavilla MV, Sánchez-Campos S, Tuñón MJ. Fruit polyphenols, immunity and inflammation. Br J Nutr 2010; 104: S15-S27
    CrossrefPubMedGoogle Scholar
  • 5 Sun J, Chu YF, Wu X, Liu RH. Antioxidant and antiproliferative activities of common fruits. J Agric Food Chem 2002; 50: 7449-7454
    CrossrefPubMedGoogle Scholar
  • 6 Ruf JC. Overview of epidemiological studies on wine, health and mortality. Drugs Exp Clin Res 2003; 29: 173-179
    PubMedGoogle Scholar
  • 7 Lippi G, Franchini M, Favaloro EJ, Targher G. Moderate red wine consumption and cardiovascular disease risk: beyond the “French paradox”. Semin Thromb Hemost 2010; 36: 59-70
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Da Luz PL, Coimbra SR. Wine, alcohol and atherosclerosis: clinical evidences and mechanisms. Braz J Med Biol Res 2004; 37: 1275-1295
    CrossrefPubMedGoogle Scholar
  • 9 Auger C, Gérain P, Laurent-Bichon F, Portet K, Bornet A, Caporiccio B, Cros G, Teissedre PL, Rouanet JM. Phenolics from commercialized grape extracts prevent early atherosclerotic lesions in hamsters by mechanisms other than antioxidant effect. J Agric Food Chem 2004; 52: 5297-5302
    CrossrefPubMedGoogle Scholar
  • 10 Rosenkranz S, Knirel D, Dietrich H, Flesch M, Erdmann E, Böhm M. Inhibition of the PDGF receptor by red wine flavonoids provides a molecular explanation for the “French paradox”. FASEB J 2002; 16: 1958-1960
    PubMedGoogle Scholar
  • 11 Ghosh D, Scheepens A. Vascular action of polyphenols. Mol Nutr Food Res 2009; 53: 322-331
    CrossrefPubMedGoogle Scholar
  • 12 Delmas D, Jannin B, Latruffe N. Vascular and ageing protective effects of resveratrol. Mol Nutr Food Res 2005; 49: 377-395
    CrossrefPubMedGoogle Scholar
  • 13 Wang S, Meckling KA, Marcone MF, Kakuda Y, Tsao R. Synergistic, additive, and antagonistic effects of food mixtures on total antioxidant capacities. J Agric Food Chem 2011; 59: 960-968
    CrossrefPubMedGoogle Scholar
  • 14 Ma XH, Zheng CJ, Han LY, Xie B, Jia J, Cao ZW, Li YX, Chen YZ. Synergistic therapeutic actions of herbal ingredients and their mechanisms from molecular interaction and network perspectives. Drug Discov Today 2009; 14: 579-588
    CrossrefPubMedGoogle Scholar
  • 15 Pignatelli P, Ghiselli A, Buchetti B, Carnevale R, Natella F, Germanò G, Fimognari F, Di Santo S, Lenti L, Violi F. Polyphenols synergistically inhibit oxidative stress in subjects given red and white wine. Atherosclerosis 2006; 188: 77-83
    CrossrefPubMedGoogle Scholar
  • 16 Wallerath T, Li H, Gödtel-Ambrust U, Schwarz PM, Förstermann U. A blend of polyphenolic compounds explains the stimulatory effect of red wine on human endothelial NO synthase. Nitric Oxide 2005; 12: 97-104
    CrossrefPubMedGoogle Scholar
  • 17 Manach C, Mazur A, Scalbert A. Polyphenols and prevention of cardiovascular diseases. Curr Opin Lipidol 2005; 16: 77-84
    CrossrefPubMedGoogle Scholar
  • 18 Scalbert A, Manach C, Morand C, Rémésy C, Jiménez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr 2005; 45: 287-306
    CrossrefPubMedGoogle Scholar
  • 19 Lee B, Moon SK. Resveratrol inhibits TNF-alpha-induced proliferation and matrix metalloproteinase expression in human vascular smooth muscle cells. J Nutr 2005; 135: 2767-2773
    PubMedGoogle Scholar
  • 20 Corder R, Crozier A, Kroon PA. Drinking your health? Itʼs too early to say. Nature 2003; 426: 119
    PubMedGoogle Scholar
  • 21 Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 2006; 58: 621-681
    CrossrefPubMedGoogle Scholar
  • 22 Haider UGB, Sorescu D, Griendling KK, Vollmar AM, Dirsch VM. Resveratrol increases serine15-phosphorylated but transcriptionally impaired p 53 and induces a reversible DNA replication block in serum-activated vascular smooth muscle cells. Mol Pharmacol 2003; 63: 925-932
    CrossrefPubMedGoogle Scholar
  • 23 Ekshyyan VP, Hebert VY, Khandelwal A, Dugas TR. Resveratrol inhibits rat aortic vascular smooth muscle cell proliferation via estrogen receptor dependent nitric oxide production. J Cardiovasc Pharmacol 2007; 50: 83-93
    CrossrefPubMedGoogle Scholar
  • 24 Cai JB, Zhang ZH, Xu DJ, Qian ZY, Wang ZR, Huang YZ, Zou JG, Cao KJ. Negative regulation of quinone reductase 2 by resveratrol in cultured vascular smooth muscle cells. Clin Exp Pharmacol Physiol 2008; 35: 1419-1425
    PubMedGoogle Scholar
  • 25 Mizutani K, Ikeda K, Yamori Y. Resveratrol inhibits AGEs-induced proliferation and collagen synthesis activity in vascular smooth muscle cells from stroke-prone spontaneously hypertensive rats. Biochem Biophys Res Commun 2000; 274: 61-66
    CrossrefPubMedGoogle Scholar
  • 26 Brito PM, Devillard R, Nègre-Salvayre A, Almeida LM, Dinis TC, Salvayre R, Augé N. Resveratrol inhibits the mTOR mitogenic signaling evoked by oxidized LDL in smooth muscle cells. Atherosclerosis 2009; 205: 126-134
    CrossrefPubMedGoogle Scholar
  • 27 Moon SK, Cho GO, Jung SY, Gal SW, Kwon TK, Lee YC, Madamanchi NR, Kim CH. Quercetin exerts multiple inhibitory effects on vascular smooth muscle cells: role of ERK1/2, cell-cycle regulation, and matrix metalloproteinase-9. Biochem Biophys Res Commun 2003; 301: 1069-1078
    CrossrefPubMedGoogle Scholar
  • 28 Kim DW, Park YS, Kim YG, Piao H, Kwon JS, Hwang KK, Youn TJ, Park JB, Yun YP, Sachinidis A, Kim CH, Cho MC, Ahn HY. Local delivery of green tea catechins inhibits neointimal formation in the rat carotid artery injury model. Heart Vessels 2004; 19: 242-247
    PubMedGoogle Scholar
  • 29 Man-Ying Chan M, Mattiacci JA, Hwang HS, Shah A, Fong D. Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway. Biochem Pharmacol 2000; 60: 1539-1548
    CrossrefPubMedGoogle Scholar
  • 30 Pedrielli P, Skibsted LH. Antioxidant synergy and regeneration effect of quercetin, (−)-epicatechin, and (+)-catechin on α-tocopherol in homogeneous solutions of peroxidating methyl linoleate. J Agric Food Chem 2002; 50: 7138-7144
    CrossrefPubMedGoogle Scholar
  • 31 Mertens-Talcott SU, Percival SS. Ellagic acid and quercetin interact synergistically with resveratrol in the induction of apoptosis and cause transient cell cycle arrest in human leukemia cells. Cancer Lett 2005; 218: 141-151
    CrossrefPubMedGoogle Scholar
  • 32 Yang JY, Della-Fera MA, Rayalam S, Ambati S, Hartzell DL, Park HJ, Baile CA. Enhanced inhibition of adipogenesis and induction of apoptosis in 3 T3-L1 adipocytes with combinations of resveratrol and quercetin. Life Sci 2008; 82: 1032-1039
    CrossrefPubMedGoogle Scholar
  • 33 Sawai Y, Moon JH. NMR analytical approach to clarify the molecular mechanisms of the antioxidative and radical-scavenging activities of antioxidants in tea using 1,1-diphenyl-2-picrylhydrazyl. J Agric Food Chem 2000; 48: 6247-6253
    CrossrefPubMedGoogle Scholar
  • 34 Zimmermann GR, Lehár J, Keith CT. Multi-target therapeutics: when the whole is greater than the sum of the parts. Drug Discov Today 2007; 12: 34-42
    CrossrefPubMedGoogle Scholar
  • 35 Kleinedler JJ, Foley JD, Alexander JS, Roerig SC, Hebert VY, Dugas TR. Synergistic effect of resveratrol and quercetin released from drug-eluting polymer coatings for endovascular devices. J Biomed Mater Res B Appl Biomater 2011; 99: 266-275
    PubMedGoogle Scholar