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Anti-platelet effects of Artesunate through Regulation of Cyclic Nucleotide on Collagen-induced Human Platelets

  • Dong-Ha Lee (Department of Biomedical Laboratory Science, Molecular Diagnostics Research Institute, Namseoul University)
  • Received : 2022.12.23
  • Accepted : 2023.03.28
  • Published : 2023.03.31

Abstract

Discovery of new substance that can regulate platelet aggregation or suppress aggregation will aid in the prevention and treatment of cardiovascular diseases. Artesunate is a compound from plant roots of Artemisia or Scopolia, and its effects have shown to be promising in areas of anticancer and Alzheimer's disease. However, the role and mechanisms by which artesunate affects the aggregation of platelets, and the formation of a thrombus are currently not understood. This study examined the ways artesunate affects platelets activation and thrombus formation induced by collagen. As a result, cAMP and cGMP production were increased significantly by artesunate relative to the doses, as well as phosphorylated VASP and IP3R, substrates to cAMP-dependent kinase and cGMP-dependent kinase, in a significant manner. The Ca2+ normally mobilized from the dense tubular system was inhibited due to IP3R, phosphorylation from artesunate, and phosphorylated VASP aided in inhibiting platelet activity via αIIb/β3 platelet membrane inactivation and inhibiting fibrinogen binding. Finally, artesunate inhibited thrombin-induced thrombus formation. Therefore, we suggest that artesunate has importance with cardiovascular diseases stemming from the abnormal platelets activation and thrombus formation by acting as an effective prophylactic and therapeutic agent.

Keywords

Acknowledgement

Funding for this paper was provided by Namseoul University year 2022.

References

  1. Cavallini L, Coassin M, Borean A, Alexandre A. Prostacyclin and sodium nitroprusside inhibit the activity of the platelet inositol 1,4,5-trisphosphate receptor and promote its phosphorylation. J Biol Chem. 1996. 271: 5545-5551. https://doi.org/10.1074/jbc.271.10.5545
  2. Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985. 260: 3440-3450. https://doi.org/10.1016/S0021-9258(19)83641-4
  3. Jackson SP. Arterial thrombosis-insidious, unpredictable and deadly. Nat Med. 2011. 17: 1423-1436. https://doi.org/10.1038/nm.2515
  4. Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol. 2009. 103: 4A-10A. https://doi.org/10.1016/j.amjcard.2008.11.017
  5. Kuo JF, Andersson RG, Wise BC, Mackerlova L, Salomonsson I, Brackett NL, et al. Calcium-dependent 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
  6. Laurent V, Loisel TP, Harbeck B, Wehman A, Grobe L, Jockusch BM, Frank JW, Gertler B, Carlier MF. Role of proteins of the Ena/VASP family in actin-based motility of Listeria monocytogenes. J Cell Biol. 1999. 144: 1245-1258. https://doi.org/10.1083/jcb.144.6.1245
  7. Lu H, Wang B, Cui N, Zhang Y. Artesunate suppresses oxidative and inflammatory processes by activating Nrf2 and ROSdependent p38 MAPK and protects against cerebral ischemiareperfusion injury. Mol Med Rep. 2018. 17: 6639-6646. https://doi.org/10.3892/mmr.2018.8666
  8. Morello F, Perino A, Hirsch E. Phosphoinositide 3-kinase signalling in the vascular system. Cardiovasc Res. 2009. 82: 261-271. https://doi.org/10.1093/cvr/cvn325
  9. Napenas J, Oost FC, DeGroot A, Loven B, Hong CH, Brennan MT, et al. 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
  10. 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: 1069-1074. https://doi.org/10.1016/S0006-2952(00)00417-2
  11. 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: 246-258. https://doi.org/10.1055/s-0037-1616222
  12. Quinton TM, Dean WL. Cyclic AMP-dependent phosphorylation of the inositol-1,4,5-trisphosphate receptor inhibits Ca2+ release from platelet membranes. Biochemical and Biochem Biophys Res Commun. 1992. 184: 893-899. https://doi.org/10.1016/0006-291X(92)90675-B
  13. Sabatine MS, Jang IK. The use of glycoprotein IIb/IIIa inhibitors in patients with coronary artery disease. Am J Med. 2000. 109: 224-237. https://doi.org/10.1016/S0002-9343(00)00474-5
  14. Schwartz SM, Heimark RL, Majesky MW. Developmental mechanisms underlying pathology of arteries. Physiol Rev. 1990. 70: 1177-1209. https://doi.org/10.1152/physrev.1990.70.4.1177
  15. Schwarz UR, Walter U, Eigenthaler M. Taming platelets with cyclic nucleotides. Biochem Pharmacol. 2001. 62: 1153-1161. https://doi.org/10.1016/S0006-2952(01)00760-2
  16. Shin JH, Kwon HW, Lee DH. Ginsenoside F4 inhibits platelet aggregation and thrombus formation by dephosphorylation of IP3RI and VASP. J Appl Biol Chem. 2019. 62: 93-100. https://doi.org/10.3839/jabc.2019.014
  17. Sudo T, Ito H, Kimura Y. Phosphorylation of the vasodilatorstimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets. 2003. 14: 381-390. https://doi.org/10.1080/09537100310001598819
  18. Thanaketpaisarn O, Waiwut P, Sakurai H, Saiki I. Artesunate enhances TRAIL-induced apoptosis in human cervical carcinoma cells through inhibition of the NF-κB and PI3K/Akt signaling pathways. Int J Oncol. 2011. 39: 279-285.
  19. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. The Lancet. 1999. 353: 227-231. https://doi.org/10.1016/S0140-6736(98)11086-3
  20. VargaSzabo D, Braun A, Nieswandt B. Calcium signaling in platelets. J Thromb Haemost. 2009. 7: 1057-1066. https://doi.org/10.1111/j.1538-7836.2009.03455.x
  21. Wangorsch G, Butt E, Mark R, Hubertus K, Geiger J, Dandekar T, et al. Time-resolved in silico modeling of finetuned cAMP signaling in platelets: feedback loops, titrated phospho-rylations and pharmacological modulation. BMC Syst Biol. 2011. 5: 178.