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Vasodilator-stimulated phosphoprotein-phosphorylation by ginsenoside Ro inhibits fibrinogen binding to αIIb/β3 in thrombin-induced human platelets

  • Shin, Jung-Hae (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, Inje University) ;
  • Kwon, Hyuk-Woo (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, Inje University) ;
  • Cho, Hyun-Jeong (Department of Biomedical Laboratory Science, College of Medical Science, Konyang University) ;
  • Rhee, Man Hee (Laboratory of Veterinary Physiology and Signaling, College of Veterinary Medicine, Kyungpook National University) ;
  • Park, Hwa-Jin (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, Inje University)
  • Received : 2015.07.20
  • Accepted : 2015.11.20
  • Published : 2016.10.15

Abstract

Background: Glycoprotein IIb/IIIa (${\alpha}aIIb/{\beta}_3$) is involved in platelet adhesion, and triggers a series of intracellular signaling cascades, leading to platelet shape change, granule secretion, and clot retraction. In this study, we evaluated the effect of ginsenoside Ro (G-Ro) on the binding of fibrinogen to ${\alpha}aIIb/{\beta}_3$. Methods: We investigated the effect of G-Ro on regulation of signaling molecules affecting the binding of fibrinogen to ${\alpha}aIIb/{\beta}_3$, and its final reaction, clot retraction. Results: We found that G-Ro dose-dependently inhibited thrombin-induced platelet aggregation and attenuated the binding of fibrinogen to ${\alpha}aIIb/{\beta}_3$ by phosphorylating cyclic adenosine monophosphate (cAMP)-dependently vasodilator-stimulated phosphoprotein (VASP; $Ser^{157}$). In addition, G-Ro strongly abrogated the clot retraction reflecting the intensification of thrombus. Conclusion: We demonstrate that G-Ro is a beneficial novel compound inhibiting ${\alpha}aIIb/{\beta}_3$-mediated fibrinogen binding, and may prevent platelet aggregation-mediated thrombotic disease.

Keywords

References

  1. van Willigen G, Akkerman JW. Protein kinase C and cyclic AMP regulate reversible exposure of binding sites for fibrinogen on the glycoprotein IIB-IIIA complex of human platelets. Biochem J 1991;273:115-20. https://doi.org/10.1042/bj2730115
  2. 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
  3. Phillips DR, Nannizzi-Alaimo L, Prasad KS. Beta3 tyrosine phosphorylation in alphaIIbbeta3 (platelet membrane GP IIb-IIIa) outside-in integrin signaling. Thromb Haemost 2001;86:246-58. https://doi.org/10.1055/s-0037-1616222
  4. Laurent V, Loisel TP, Harbeck B, Wehman A, Grobe L, Jockusch BM, Wehland J, Gertler FB, Carlier MF. Role of proteins of the Ena/VASP family in actin-based motility of Listeria monocytogenes. J Cell Biol 1999;144:1245-58. https://doi.org/10.1083/jcb.144.6.1245
  5. Sudo T, Ito H, Kimura Y. Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets 2003;14:381-90. https://doi.org/10.1080/09537100310001598819
  6. Kamruzzaman SM, Yayeh T, Ji HD, Park JY, Kwon YS, Lee IK, Rhee MH. p-Terphenyl curtisian E inhibits in vitro platelet aggregation via cAMP elevation and VASP phosphorylation. Vasc Pharmacol 2013;59:83-9. https://doi.org/10.1016/j.vph.2013.07.002
  7. Oh WJ, Endale M, Park SC, Cho JY, Rhee MH. Dual roles of quercetin in platelets: phosphoinositide-3-kinase and MAP kinases inhibition, and cAMP-dependent vasodilator-stimulated phosphoprotein stimulation. Evid Based Complement Alternat Med 2012;2012:485262.
  8. Lincoff AM, Califf RM, Topol EJ. Platelet glycoprotein IIb/IIIa receptor blockade in coronary artery disease. J Am Coll Cardiol 2000;35:1103-15. https://doi.org/10.1016/S0735-1097(00)00554-4
  9. Sabatine MS, Jang IK. The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease. Am J Med 2000;109:224-37. https://doi.org/10.1016/S0002-9343(00)00474-5
  10. Sanada S, Kondo N, Shoji J, Tanaka O, Shibata S. Studies on the saponins of ginseng. I. Structures of ginsenoside-Ro, -Rb1, -Rb2, -Rc and -Rd. Chem Pharm Bull 1974;22:421-8. https://doi.org/10.1248/cpb.22.421
  11. Choi KT. Botanical characteristics, pharmacological effects and medicinal components of Korean Panax ginseng CA Meyer. Acta Pharmacol Sin 2008;29:1109-18. https://doi.org/10.1111/j.1745-7254.2008.00869.x
  12. Matsuda H, Namba K, Fukuda S, Tani T, Kubo M. Pharmacological study on Panax ginseng CA Meyer. III. Effects of Red Ginseng on experimental disseminated intravascular coagulation. (2). Effects of ginsenosides on blood coagulative and fibrinolytic systems. Chem Pharm Bull 1986;34:1153-7. https://doi.org/10.1248/cpb.34.1153
  13. Matsuda H, Namba K, Fukuda S, Tani T, Kubo M. Pharmacological study on Panax ginseng CA Meyer. IV. Effects of red ginseng on experimental disseminated intravascular coagulation. (3). Effect of ginsenoside-Ro on the blood coagulative and fibrinolytic system. Chem Pharm Bull 1986;34:2100-4. https://doi.org/10.1248/cpb.34.2100
  14. Teng CM, Kuo SC, Ko FN, Lee JC, Lee LG, Chen SC, Huang TF. Antiplatelet actions of panaxynol and ginsenosides isolated from ginseng. Biochim Biophys Acta 1989;990:315-20. https://doi.org/10.1016/S0304-4165(89)80051-0
  15. Shin JH, Kwon HW, Cho HJ, Rhee MH, Park HJ. Inhibitory effects of total saponin from Korean Red Ginseng on $[Ca^{2+}]_i$ mobilization through phosphorylation of cyclic adenosine monophosphate-dependent protein kinase catalytic subunit and inositol 1, 4, 5-trisphosphate receptor type I in human platelets. J Ginseng Res 2015;39:354-64. https://doi.org/10.1016/j.jgr.2015.03.006
  16. Gambaryan S, Kobsar A, Rukoyatkina N, Herterich S, Geiger J, Smolenski A, Walter U. Thrombin and collagen induce a feedback inhibitory signaling pathway in platelets involving dissociation of the catalytic subunit of protein kinase a from an $NF{\kappa}B-I{\kappa}B$ complex. J Biol Chem 2010;285:18352-63. https://doi.org/10.1074/jbc.M109.077602
  17. Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Eigenthaler M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator-stimulated phosphoprotein phosphorylation. Catheter Cardiovasc Interv 2003;59:295-302. https://doi.org/10.1002/ccd.10497
  18. Smolenski A, Bachmann C, Reinhard K, Honig-Liedl P, Jarchau T, Hoschuetzky H, Walter U. Analysis and regulation of vasodilator-stimulated phosphoprotein serine239 phosphorylation in vitro and in intact cells using a phosphor specific monoclonal antibody. J Biol Chem 1998;273:20029-35. https://doi.org/10.1074/jbc.273.32.20029
  19. Law DA, DeGuzman FR, Heiser P, Ministri-Madrid K, Killeen N, Phillips DR. Integrin cytoplasmic tyrosine motif is required for outside-in ${\alpha}IIb{\beta}3$ signalling and platelet function. Nature 1999;401:808-11. https://doi.org/10.1038/44599
  20. Leclerc JR. Platelet glycoprotein IIb/IIIa antagonists: lessons learned from clinical trials and future directions. Crit Care Med 2002;30:332-40. https://doi.org/10.1097/00003246-200205001-00025
  21. Estevez B, Shen B, Du X. Targeting integrin and integrin signaling in treating thrombosis. Arterioscler Thromb Vasc Biol 2015;35:24-9. https://doi.org/10.1161/ATVBAHA.114.303411
  22. Kwon HW, Shin JH, Lee DH, Park HJ. Inhibitory effects of cytosolic $Ca^{2+}$ concentration by ginsenoside Ro are dependent on phosphorylation of IP3RI and dephosphorylation of ERK in human platelets. Evid Based Complement Alternat Med 2015;2015:764906.
  23. Fox JE, Taylor RG, Taffarel M, Boyles JK, Goll DE. Evidence that activation of platelet calpain is induced as a consequence of binding of adhesive ligand to the integrin, glycoprotein IIb-IIIa. J Cell Biol 1993;120:1501-7. https://doi.org/10.1083/jcb.120.6.1501
  24. Matter CM, Schuler PK, Alessi P, Meier P, Ricci R, Zhang D, Luscher TF. Molecular imaging of atherosclerotic plaques using a human antibody against the extra-domain B of fibronectin. Circ Res 2004;95:1225-33. https://doi.org/10.1161/01.RES.0000150373.15149.ff
  25. Bultmann A, Li Z, Wagner S, Peluso M, Schonberger T, Weis C, Munch G. Impact of glycoprotein VI and platelet adhesion on atherosclerosis-a possible role of fibronectin. J Mol Cell Cardiol 2010;49:532-42. https://doi.org/10.1016/j.yjmcc.2010.04.009
  26. Castro-Malaspina H, Rabellino EM, Yen A, Nachman RL, Moore MA. Human megakaryocyte stimulation of proliferation of bone marrow fibroblasts. Blood 1981;57:781-7.
  27. Holash J, Maisonpierre PC, Compton D, Boland P, Alexander CR, Zagzag D, Yancopoulos GD, Wiegand SJ. Vessel cooption, regression, and growth in tumors mediated by angiopoietins and VEGF. Science 1999;284:1994-8. https://doi.org/10.1126/science.284.5422.1994
  28. Seppa H, Grotendorst G, Seppa S, Schiffmann E, Martin GR. Platelet-derived growth factor in chemotactic for fibroblasts. J Cell Biol 1982;92:584-8. https://doi.org/10.1083/jcb.92.2.584
  29. Schwartz SM, Ross R. Cellular proliferation in atherosclerosis and hypertension. Prog Cardiovasc Dis 1984;26:355-72. https://doi.org/10.1016/0033-0620(84)90010-0
  30. Packham MA, Mustard JF. The role of platelets in the development and complications of atherosclerosis. Semin Hematol 1986;23:8-26.
  31. Schwartz SM, Reidy MA. Common mechanisms of proliferation of smooth muscle in atherosclerosis and hypertension. Hum Pathol 1987;18:240-7. https://doi.org/10.1016/S0046-8177(87)80006-0
  32. Nagai R, Suzuki T, Aizawa K, Shindo T, Manabe I. Significance of the transcription factor KLF5 in cardiovascular remodeling. J Thromb Haemost 2005;3:1569-76. https://doi.org/10.1111/j.1538-7836.2005.01366.x
  33. Phillips DR, Conley PB, Sinha U, Andre P. Therapeutic approaches in arterial thrombosis. J Thromb Haemost 2005;3:1577-89. https://doi.org/10.1111/j.1538-7836.2005.01418.x
  34. Davi G, Patrono C. Platelet activation and atherothrombosis. New Engl J Med 2007;357:2482-94. https://doi.org/10.1056/NEJMra071014
  35. Matsuda H, Samukawa KI, Kubo M. Anti-inflammatory activity of ginsenoside Ro. Planta Med 1990;56:19-23. https://doi.org/10.1055/s-2006-960875
  36. Kim S, Oh MH, Kim BS, Kim WI, Cho HS, Park BY, Kwon J. Upregulation of heme oxygenase-1 by ginsenoside Ro attenuates lipopolysaccharide-induced inflammation in macrophage cells. J Ginseng Res 2015;39:365-70. https://doi.org/10.1016/j.jgr.2015.03.008

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