Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
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The inhibitory activity of ginsenoside Rp4 in adenosine diphosphate-induced platelet aggregation

  • Son, Young-Min (Laboratory of Veterinary Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Jeong, Da-Hye (Laboratory of Veterinary Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Park, Hwa-Jin (Department of Biomedical Laboratory Science, College of Biomedical Science, Inje University) ;
  • Rhee, Man-Hee (Laboratory of Veterinary Physiology and Cell Signaling, College of Veterinary Medicine, Kyungpook National University)
  • Received : 2015.12.04
  • Accepted : 2016.01.26
  • Published : 2017.01.15
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Abstract

Background: Korean ginseng, Panax ginseng Meyer, has been used as a traditional oriental medicine to treat illness and promote health for several thousand years. Ginsenosides are the main constituents for the pharmacological effects of P. ginseng. Since several ginsenosides, including ginsenoside (G)-Rg3 and G-Rp1, have reported antiplatelet activity, here we investigate the ability of G-Rp4 to modulate adenosine diphosphate (ADP)-induced platelet aggregation. The ginsenoside Rp4, a similar chemical structure of G-Rp1, was prepared from G-Rg1 by chemical modification. Methods: To examine the effects of G-Rp4 on platelet activation, we performed several experiments, including antiplatelet ability, the modulation of intracellular calcium concentration, and P-selectin expression. In addition, we examined the activation of integrin ${\alpha}IIb{\beta}_3$ and the phosphorylation of signaling molecules using fibrinogen binding assay and immunoblotting in rat washed platelets. Results: G-Rp4 inhibited ADP-induced platelet aggregation in a dose-dependent manner. We found that G-Rp4 decreased calcium mobilization and P-selectin expression in ADP-activated platelets. Moreover, fibrinogen binding to integrin ${\alpha}IIb{\beta}_3$ by ADP was attenuated in G-Rp4-treated platelets. G-Rp4 significantly attenuated phosphorylation of extracellular signal-regulated protein kinases 1 and 2, p38, and c-Jun N-terminal kinase, as well as protein kinase B, phosphatidylinositol 3-kinase, and phospholipase C-${\gamma}$ phosphorylations. Conclusion: G-Rp4 significantly inhibited ADP-induced platelet aggregation and this is mediated via modulating the intracellular signaling molecules. These results indicate that G-Rp4 could be a potential candidate as a therapeutic agent against platelet-related cardiovascular diseases.

Keywords

References

  1. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in developing countries. Circulation 1998;97:596-601. https://doi.org/10.1161/01.CIR.97.6.596
  2. McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet 1991;337:382-6. https://doi.org/10.1016/0140-6736(91)91164-P
  3. Davi G, Patrono C. Platelet activation and atherothrombosis. N Engl J Med 2007;357:2482-94. https://doi.org/10.1056/NEJMra071014
  4. Furie B, Furie BC. Mechanisms of thrombus formation. N Engl J Med 2008;359:938-49. https://doi.org/10.1056/NEJMra0801082
  5. Adam F, Kauskot A, Rosa JP, Bryckaert M. Mitogen-activated protein kinases in hemostasis and thrombosis. J Thromb Haemost 2008;6:2007-16. https://doi.org/10.1111/j.1538-7836.2008.03169.x
  6. Dovizio M, Alberti S, Guillem-Llobat P, Patrignani P. Role of platelets in inflammation and cancer: novel therapeutic strategies. Basic Clin Pharmacol Toxicol 2014;114:118-27. https://doi.org/10.1111/bcpt.12156
  7. Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005;115:3378-84. https://doi.org/10.1172/JCI27196
  8. Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003;9:61-7. https://doi.org/10.1038/nm810
  9. Ruggeri ZM. Platelets in atherothrombosis. Nat Med 2002;8:1227-34. https://doi.org/10.1038/nm1102-1227
  10. Moheimani F, Jackson DE. P2Y12 receptor: platelet thrombus formation and medical interventions. Int J Hematol 2012;96:572-87. https://doi.org/10.1007/s12185-012-1188-5
  11. Endale M, Lee WM, Kamruzzaman SM, Kim SD, Park JY, Park MH, Park TY, Park HJ, Cho JY, Rhee MH. Ginsenoside-Rp1 inhibits platelet activation and thrombus formation via impaired glycoprotein VI signalling pathway, tyrosine phosphorylation and MAPK activation. Br J Pharmacol 2012;167:109-27. https://doi.org/10.1111/j.1476-5381.2012.01967.x
  12. Attele AS, Wu JA, Yuan C-S. Ginseng pharmacology: Multiple constituents and multiple actions. Biochemical Pharmacology 1999;58:1685-93. https://doi.org/10.1016/S0006-2952(99)00212-9
  13. Jung KY, Kim DS, Oh SR, Lee IS, Lee JJ, Park JD, Kim SI, Lee HK. Platelet activating factor antagonist activity of ginsenosides. Biol Pharm Bull 1998;21:79-80. https://doi.org/10.1248/bpb.21.79
  14. Zhang W, Chen G, Deng CQ. Effects and mechanisms of total Panax notoginseng saponins on proliferation of vascular smooth muscle cells with plasma pharmacology method. J Pharm Pharmacol 2012;64:139-45. https://doi.org/10.1111/j.2042-7158.2011.01379.x
  15. Lee HS, Kim SD, Lee WM, Endale M, Kamruzzaman SM, Oh WJ, Cho JY, Kim SK, Cho HJ, Park HJ, et al. A noble function of BAY 11-7082: Inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. Eur J Pharmacol 2010;627:85-91. https://doi.org/10.1016/j.ejphar.2009.11.005
  16. Lee DH, Cho HJ, Kang HY, Rhee MH, Park HJ. Total saponin from Korean red ginseng inhibits thromboxane A2 production associated microsomal enzyme activity in platelets. J Ginseng Res 2012;36:40-6. https://doi.org/10.5142/jgr.2012.36.1.40
  17. Park JY, Oh WJ, Kim MJ, Kim TH, Cho JY, Park HJ, Lee IK, Kim S, Kim GS, Kim SK, et al. Mechanism of anti-platelet activity of Oligoporus tephroleucus oligoporin A: involvement of extracellular signal-regulated kinase phosphorylation and cyclic nucleotide elevation. Platelets 2012;23:376-85. https://doi.org/10.3109/09537104.2011.629309
  18. Park JY, Ji HD, Jeon BR, Im EJ, Son YM, Lee JY, Lee DH, Lee YC, Hyun E, Jia Q, et al. Chlorin -6 prevents ADP-induced platelet aggregation by decreasing PI3K-Akt phosphorylation and promoting cAMP production. Evid Based Complement Alternat Med 2013;2013:569160.
  19. Schaeffer J, Blaustein MP. Platelet free calcium concentrations measured with fura-2 are influenced by the transmembrane sodium gradient. Cell Calcium 1989;10:101-13. https://doi.org/10.1016/0143-4160(89)90050-X
  20. Phillips DR, Baughan AK. Fibrinogen binding to human platelet plasma membranes. Identification of two steps requiring divalent cations. J Biol Chem 1983;258:10240-6.
  21. Obergfell AEK, Mocsai A, Buensuceso C, Moores SL, Brugge JS, Lowell CA, Shattil SJ. Coordinate interactions of Csk, Src, and Syk kinases with aIIbb3 initiate integrin signaling to the cytoskeleton. J Cell Biol 2002:265-75.
  22. Wonerow PPA, Vaux DJ, Watson SP. A critical role for phospholipase Cc2 in aIIbb3-mediated platelet spreading. J Biol Chem 2003:37520-9.
  23. Arias-Salgado EG, Lizano S, Sarkar S, Brugge JS, Ginsberg MH, Shattil SJ. Src kinase activation by direct interaction with the integrin beta cytoplasmic domain. Proc Natl Acad Sci U S A 2003;100:13298-302. https://doi.org/10.1073/pnas.2336149100
  24. Calderwood DA. Integrin activation. J Cell Sci 2004;117:657-66. https://doi.org/10.1242/jcs.01014
  25. Canobbio ISL, Cipolla L, Ciraolo E, Gruppi C, Balduini C, Torti M. Genetic evidence for a predominant role of PI3Kb catalytic activity in ITAM- and integrinmediated signaling in platelets. Blood 2009:2193-6.
  26. Suzuki-Inoue KHC, Inoue O, Kaneko M, Cuyun-Lira O, Takafuta T, Watson SP, Ozaki Y. Involvement of Src kinases and $PLC{\gamma}2$ in clot retraction. Thromb Res 2007;120:251-8. https://doi.org/10.1016/j.thromres.2006.09.003
  27. Woulfe DS. Akt signaling in platelets and thrombosis. Expert Rev Hematol 2010;3:81-91. https://doi.org/10.1586/ehm.09.75
  28. Zahid MS, Waise TM, Kamruzzaman M, Ghosh AN, Nair GB, Mekalanos JJ, Faruque SM. The cyclic AMP (cAMP)-cAMP receptor protein signaling system mediates resistance of Vibrio cholerae O1 strains to multiple environmental bacteriophages. Appl Environ Microbiol 2010;76:4233-40. https://doi.org/10.1128/AEM.00008-10
  29. Jackson EC, McNicol A. Cyclic nucleotides inhibit MAP kinase activity in lowdose collagen-stimulated platelets. Thromb Res 2010;125:147-51. https://doi.org/10.1016/j.thromres.2009.06.004
  30. Smolenski A. Novel roles of cAMP/cGMP-dependent signaling in platelets. J Thromb Haemost 2012;10:167-76. https://doi.org/10.1111/j.1538-7836.2011.04576.x
  31. Mangin P, Nonne C, Eckly A, Ohlmann P, Freund M, Nieswandt B, Cazenave JP, Gachet C, Lanza F. A PLC gamma 2-independent platelet collagen aggregation requiring functional association of GPVI and integrin alpha2beta1. FEBS Lett 2003;542:53-9. https://doi.org/10.1016/S0014-5793(03)00337-5
  32. Leung KW, Cheng YK, Mak NK, Chan KK, Fan TP, Wong RN. Signaling pathway of ginsenoside-Rg1 leading to nitric oxide production in endothelial cells. FEBS Lett 2006;580:3211-6. https://doi.org/10.1016/j.febslet.2006.04.080
  33. Cheng Y, Shen LH, Zhang JT. Anti-amnestic and anti-aging effects of ginsenoside Rg1 and Rb1 and its mechanism of action. Acta Pharmacol Sin 2005;26:143-9. https://doi.org/10.1111/j.1745-7254.2005.00034.x
  34. Lee WM, Kim SD, Park MH, Cho JY, Park HJ, Seo GS, Rhee MH. Inhibitory mechanisms of dihydroginsenoside Rg3 in platelet aggregation: critical roles of ERK2 and cAMP. J Pharm Pharmacol 2008;60:1531-6. https://doi.org/10.1211/jpp.60.11.0015
  35. Liu R, Xing D, Lu H, Wu H, Du L. Pharmacokinetics of puerarin and ginsenoside Rg1 of CBN injection and the relation with platelet aggregation in rats. Am J Chin Med 2006;34:1037-45. https://doi.org/10.1142/S0192415X06004508
  36. Oh WJ, Endale M, Park SC, Cho JY, Rhee MH. Dual Roles of quercetin in platelets: phosphoinositide-3-kinase and MAP kinases inhibition, and cAMPdependent vasodilator-stimulated phosphoprotein stimulation. Evid Based Complement Alternat Med 2012;2012:485262.
  37. Roger S, Pawlowski M, Habib A, Jandrot-Perrus M, Rosa JP, Bryckaert M. Costimulation of the Gi-coupled ADP receptor and the Gq-coupled TXA2 receptor is required for ERK2 activation in collagen-induced platelet aggregation. FEBS Lett 2004;556:227-35. https://doi.org/10.1016/S0014-5793(03)01430-3
  38. Cimmino G, Golino P. Platelet biology and receptor pathways. J Cardiovasc Transl Res 2013;6:299-309. https://doi.org/10.1007/s12265-012-9445-9
  39. Clemetson KJ. Platelets and primary haemostasis. Thromb Res 2012;129:220-4. https://doi.org/10.1016/j.thromres.2011.11.036
  40. Lien LM, Chen ZC, Chung CL, Yen TL, Chiu HC, Chou DS, Huang SY, Sheu JR, Lu WJ, Lin KH. Multidrug resistance protein 4 (MRP4/ABCC4) regulates thrombus formation in vitro and in vivo. Eur J Pharmacol 2014;737:159-67. https://doi.org/10.1016/j.ejphar.2014.05.001
  41. Lee JJ, Han JH, Jung SH, Lee SG, Kim IS, Cuong NM, Huong TT, Khanh PN, Kim YH, Yun YP, et al. Antiplatelet action of indirubin-30-monoxime through suppression of glycoprotein VI-mediated signal transduction: a possible role for ERK signaling in platelets. Vascul Pharmacol 2014;63:182-92. https://doi.org/10.1016/j.vph.2014.10.005
  42. Lu Y, Li Q, Liu YY, Sun K, Fan JY, Wang CS, Han JY. Inhibitory effect of caffeic acid on ADP-induced thrombus formation and platelet activation involves mitogen-activated protein kinases. Sci Rep 2015;5:13824. https://doi.org/10.1038/srep13824
  43. Keane C, Petersen HJ, Tilley DO, Haworth J, Cox D, Jenkinson HF, Kerrigan SW. Multiple sites on Streptococcus gordonii surface protein PadA bind to platelet GPIIbIIIa. Thromb Haemost 2013;110:1278-87. https://doi.org/10.1160/TH13-07-0580
  44. van der Meijden PE, Feijge MA, Swieringa F, Gilio K, Nergiz-Unal R, Hamulyak K, Heemskerk JW. Key role of integrin alpha(IIb)beta (3) signaling to Syk kinase in tissue factor-induced thrombin generation. Cell Mol Life Sci 2012;69:3481-92. https://doi.org/10.1007/s00018-012-1033-2
  45. Leclerc JR. Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. Crit Care Med 2002;30:S332-40. https://doi.org/10.1097/00003246-200205001-00025
  46. Payrastre B, Missy K, Trumel C, Bodin S, Plantavid M, Chap H. The integrin alpha IIb/beta 3 in human platelet signal transduction. Biochem Pharmacol 2000;60:1069-74. https://doi.org/10.1016/S0006-2952(00)00417-2

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