Biomedical Science Letters (대한의생명과학회지)

The Korean Society for Biomedical Laboratory Sciences (대한의생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibitory Effect of Scopoletin on U46619-induced Platelet Aggregation through Regulation of Ca2+ Mobilization

  • Lee, Dong-Ha (Department of Biomedical Laboratory Science, Molecular Diagnostics Research Institute, Namseoul University)
  • Received : 2019.02.21
  • Accepted : 2019.05.22
  • Published : 2019.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Platelet aggregation is essential for hemostatic process in case of blood vessels damages. However, excessive platelet aggregation can cause cardiovascular disorders including atherosclerosis, thrombosis and myocardial infarction. Scopoletin is usually found in the roots of genus Scopolia or Artemisia, and is known to have anticoagulant and anti-malarial effects. This study investigated the effect of scopoletin on human platelet aggregation induced by U46619, an analogue of thromboxane $A_2(TXA_2)$. Scopoletin had anti-platelet effects by down-regulating $TXA_2$ and intracellular $Ca^{2+}$ mobilization ($[Ca^{2+}]_i$), the aggregation-inducing molecules generated in activated platelets. On the other hand, scopoletin increased the levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are known to be intracellular $Ca^{2+}$ antagonists. This resulted in inhibition of fibrinogen binding to ${\alpha}IIb/{\beta}_3$ in U46619-induced human platelet aggregation. In addition, scopoletin inhibited the release of adenosine trisphosphate (ATP) in dose-dependent manner. This result means that the aggregation amplification activity through the granule secretion in platelets was suppressed by scopoletin. Therefore, we demonstrated that scopoletin has a potent antiplatelet effect and is highly likely to prevent platelet-derived vascular disease.

Keywords

References

  1. Barragan P, Bouvier JL, Roquebert PO, Macaluso G, Commeau P, Comet B, Lafont A, Camoin L, Walter U, 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
  2. Berridge MJ, Irvine RF. Inositol phosphates and cell signalling. Nature. 1989. 341: 197-205. https://doi.org/10.1038/341197a0
  3. Calderwood DA, Shattil SJ, Ginsberg MH. Integrins and actin filaments: reciprocal regulation of cell adhesion and signaling. J Biol Chem. 2000. 275: 22607-22610. https://doi.org/10.1074/jbc.R900037199
  4. Cattanco M, Tenconi PM, Lecchi A, Mannucci PM. In vitro effects of picotamide on human platelet aggregation, the release reaction and thromboxane B2 production. Thromb Res. 1991. 62: 717-724. https://doi.org/10.1016/0049-3848(91)90375-7
  5. Furuichi T, Mikoshiba K. Inositol 1, 4, 5-trisphosphate receptormediated $Ca^{2+}$ signaling in the brain. J Neurochem. 1995. 64: 953-960. https://doi.org/10.1046/j.1471-4159.1995.64030953.x
  6. Gao J, Tao J, Liang W, Zhao M, Du X, Cui S, Duan H, Kan B, Su X, Jiang Z. Identification and characterization of phosphodiesterases that specifically degrade 3'3'-cyclic GMP-AMP. Cell Res. 2015. 25: 539-550. https://doi.org/10.1038/cr.2015.40
  7. Haslam RJ, Dickinson NT, Jang EK. Cyclic nucleotides and phosphodiesterases in platelets. Thromb Haemost. 1999. 82: 412-423. https://doi.org/10.1055/s-0037-1615861
  8. Holmsen H, Day HJ. The selectivity of the thrombininduced platelet release reaction: subcellular localization of released and retained constituents. J Lab Clin Med. 1970. 75: 840-855.
  9. Horstrup K, Jablonka B, Honig-Liedl P, Just M, Kochsiek K, Walter U. Phosphorylation of focal adhesion vasodilatorstimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem. 1994. 225: 21-27. https://doi.org/10.1111/j.1432-1033.1994.00021.x
  10. Kawada N, Uoya M, Seki S, Kuroki T, Kobayashi K. Regulation by cAMP of STAT1 activation in hepatic stellate cells. Biochem Biophys Res Commun. 1997. 233: 464-469. https://doi.org/10.1006/bbrc.1997.6481
  11. Kawada T, Toyosato A, Islam MO, Yoshida Y, Imai S. cGMP-kinase mediates cGMP- and cAMP-induced $Ca^{2+}$ desensitization of skinned rat artery. Eur J Pharmacol. 1997. 323: 75-82. https://doi.org/10.1016/S0014-2999(97)00028-9
  12. Kuo JF, Andersson RG, Wise BC, Mackerlova L, Salomonsson I, Brackett NL, Katoh N, Shoji M, Wrenn RW. Calciumdependent protein kinase: widespread occurrence in various tissues and phyla of the animal kingdom and comparison of effects of phospholipid, calmodulin, and trifluoperazine. Proc Natl Acad Sci. 1980. 77: 7039-7043. https://doi.org/10.1073/pnas.77.12.7039
  13. Kwon HW, Lee DH. The inhibitory effects of cordycepin on phosphoproteins including PI3K, Akt, and p38. Korean J Clin Lab Sci. 2017. 49: 99-107. https://doi.org/10.15324/kjcls.2017.49.2.99
  14. Menshikov MYU, Ivanova K, Schaefer M, Drummer C, Gerzer R. Influence of the cGMP analog 8-PCPT-cGMP on agonistinduced increases in cytosolic ionized $Ca^{2+}$ and on aggregation of human platelets. Eur J Pharmacol. 1993. 245: 281-284. https://doi.org/10.1016/0922-4106(93)90108-L
  15. Napenas J, Oost FC, DeGroot A, Loven B, Hong CH, Brennan MT, Lockhart PB, van Diermen DE. Review of postoperative bleeding risk in dental patients on antiplatelet therapy. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013. 115: 491-499. https://doi.org/10.1016/j.oooo.2012.11.001
  16. Nishikawa M, Tanaka T, Hidaka H. $Ca^{2+}$-calmodulin-dependent phosphorylation and platelet secretion. Nature. 1980. 287: 863-865. https://doi.org/10.1038/287863a0
  17. Obasi SC, Njoku OU, Obidoa O. Effects of single oral doses of scopoletin and aflatoxin B1 on the clotting time, serum cholesterol and phospholipid levels of chicks. Indian J Physiol Pharmacol. 1994. 38: 89-94.
  18. Ohkubo S, Nakahata N, Ohizumi Y. Thromboxane $A_{2}$-mediated shape change: independent of Gq-phospholipase C--115: 491-499. pathway in rabbit platelets. Br J Pharmacol. 1996. 117: 1095-1104. https://doi.org/10.1111/j.1476-5381.1996.tb16702.x
  19. Okada Y, Miyauchi N, Suzuki K, Kobayashi T, Tsutsui C, Mayuzumi K, Nishibe S, Okuyama T. Search for naturally occurring substances to prevent the complications of diabetes. II. Inhibitory effect of coumarin and flavonoid derivatives on bovine lens aldose reductase and rabbit platelet aggregation. Chem Pharm Bull. 1995. 43: 1385-7. https://doi.org/10.1248/cpb.43.1385
  20. Okwu AK, Ullian ME, Halushka PV. Homologous desensitization of human platelet thromboxane $A_{2}$/prostaglandin $H_{2}$ receptors. J Pharmacol Exp Ther. 1992. 262: 238-245.
  21. Saitoh M, Naka M, Hidaka H. The modulatory role of myosin light chain phosphorylation in human platelet activation. Biochem Biophys Res Commun. 1986. 140: 280-287. https://doi.org/10.1016/0006-291X(86)91087-9
  22. Schaeffer J, Blaustein MP. Platelet free calcium concentrations measured with fura-2 are influenced by the transmembrane sodium gradient. Cell Calcium. 1989. 10: 101-113. https://doi.org/10.1016/0143-4160(89)90050-X
  23. Smolenski A, Burkhardt AM, Eigenthaler M, Butt E, Gambaryan S, Lohmann SM, Walter U. Functional analysis of cGMPdependent protein kinases I and II as mediators of NO/cGMP effects. Naunyn Schmiedebergs Arch Pharmacol. 1998. 358: 134-139. https://doi.org/10.1007/PL00005234
  24. Su CY, Shiao MS, Wang CT. Differential effects of ganodermic acid S on the thromboxane A2-signaling pathways in human platelets. Biochem Pharmacol. 1999. 58: 587-595. https://doi.org/10.1016/S0006-2952(99)00136-7
  25. Towler MJ, Weathers PJ. Variations in key artemisinic and other metabolites throughout plant development in Artemisia annua L. for potential therapeutic use. Ind Crops Prod. 2015. 67: 185-191. https://doi.org/10.1016/j.indcrop.2015.01.007
  26. Wangorsch G, Butt E, Mark R, Hubertus K, Geiger J, Dandekar T, Dittrich M. Time-resolved in silico modeling of finetuned cAMP signaling in platelets: feedback loops, titrated phosphorylations and pharmacological modulation, BMC Syst Biol. 2011. 5: 178. https://doi.org/10.1186/1752-0509-5-178
  27. Wentworth JK, Pula G, Poole AW, Vasodilator-stimulated phosphoprotein (VASP) is phosphorylated on Ser157 by protein kinase C-dependent and -independent mechanisms in thrombinstimulated human platelets, Biochemical J. 2006. 393: 555-564. https://doi.org/10.1042/BJ20050796
  28. Wu TS, Tsang ZJ, Wu PL, Lin FW, Li CY, Teng CM, Lee KH. New constituents and antiplatelet aggregation and anti-HIV principles of Artemisia capillaris. Bioorg Med Chem. 2001. 9: 77-83. https://doi.org/10.1016/S0968-0896(00)00225-X