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Anti-platelet Effects of Artemisinin 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 : 2024.06.24
  • Accepted : 2024.08.22
  • Published : 2024.09.30

Abstract

The discovery of a novel substance capable of regulating or suppressing platelet aggregation holds significant promise for the prevention and treatment of cardiovascular diseases. Artemisinin, a compound derived from plants like Artemisia or Scopolia, has demonstrated potential across various fields, including anticancer and Alzheimer's disease research. However, its specific role and mechanisms in influencing platelet activation and thrombus formation remain incompletely understood. This study delves into elucidating how artemisinin affects platelet activation and thrombus formation. Results revealed a significant increase in cAMP production with varying doses of artemisinin, alongside notable phosphorylation of VASP and IP3R-both substrates for cAMP-dependent kinase. This phosphorylation led to the inhibition of Ca2+ mobilization from the dense tubular system, consequently reducing platelet activity via αIIb/β3 inactivation and suppressing fibrinogen binding. Furthermore, artemisinin exhibited inhibition of thrombin-induced thrombus formation. These findings suggest that artemisinin holds promise as an effective prophylactic and therapeutic agent against cardiovascular diseases, specifically targeting abnormal platelet activation and thrombus formation.

Keywords

Acknowledgement

Funding for this paper was provided by Namseoul University year 2024.

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. Cipollone F, Patrignani P, Greco A, Panara MR, Padovano R, Cuccurullo F, et al. Differential suppression of thromboxane biosynthesis by indobufen and aspirin in patients with unstable angina. Circulation. 1997. 96: 1109-1116. https://doi.org/10.1161/01.CIR.96.4.1109
  3. Das SS, Nanda GG, Alone DP. Artemisinin and curcumin inhibit Drosophila brain tumor, prolong life span, and restore locomotor activity. IUBMB Life. 2014. 66: 496-506. https://doi.org/10.1002/iub.1284
  4. Fang J, Zhao X, Li S, Xing X, Wang H, Lazarovici P, et al. Protective mechanism of artemisinin on rat bone mar-row-derived mesenchymal stem cells against apoptosis induced by hydrogen peroxide via activation of c-Raf-Erk1/2-p90(rsk)-CREB pathway. Stem Cell Research & Therapy. 2019. 10: 312.
  5. 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
  6. Jackson SP. Arterial thrombosis-insidious, unpredictable and deadly. Nat Med. 2011. 17: 1423-1436. https://doi.org/10.1038/nm.2515
  7. Jennings LK. Role of platelets in atherothrombosis. Am J Cardiol. 2009. 103: 4A-10A. https://doi.org/10.1016/j.amjcard.2008.11.017
  8. Kim HH, Jeong Hwa Hong JH, Ingkasupart P, Lee DH, Park HJ. Inhibitory Effects of Water Extract from Rice Bran Due to cAMP-dependent Phosphorylation of VASP (Ser157) on ADP-induced Platelet Aggregation. Biomed Sci Letters. 2014. 20: 129-138. https://doi.org/10.15616/BSL.2014.20.3.129
  9. Kim HH, Lee DH, Hong JH, Ingkasupart P, Nam GS, Ok WJ, Kim MJ, Yu YB, Kang HC, Park HJ. Inhibitory Effects of Rice Bran Water Extract Fermented Lactobacillus plantarum due to cAMP-dependent Phosphorylation of VASP (Ser157) on human Platelet Aggregation. Biomed Sci Letters. 2015. 21: 103-114. https://doi.org/10.15616/BSL.2015.21.2.103
  10. Ko SN, Son JW, Kim GR, Kim MS, Lee YJ, Kim SJ, Shin JH, Jo DI, Bok WY, Oh HG, Kwon HW. The inhibitory effects of Glycyrrhiza uralensis on human platelet aggregation and thrombus formation. Biomed Sci Letters. 2023. 29: 242-248. https://doi.org/10.15616/BSL.2023.29.4.242
  11. 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
  12. Lee DH. Inhibitory effects of cordycepin on platelet activation via regulation of cyclic adenosine monophosphate-downstream pathway. Biomed Sci Letters. 2017. 23: 251-260. https://doi.org/10.15616/BSL.2017.23.3.251
  13. Lee DH. Inhibitory effect of scopoletin on U46619-induced platelet aggregation through regulation of Ca2+ mobilization. Biomed Sci Letters. 2019. 25: 123-130.
  14. Lee DH. Thrombus formation Inhibition of esculetin through regulation of cyclic nucleotides on collagen-induced platelets. Biomed Sci Letters. 2021. 27: 270-276. https://doi.org/10.15616/BSL.2021.27.4.270
  15. Lee DH. Anti-platelet effects of artesunate through regulation of cyclic nucleotide on collagen-induced human platelets. Biomed Sci Letters. 2023a. 29: 41-27.
  16. Lee DH. Antithrombotic Effect of Artemisinin through Phosphoprotein Regulation in U46619-induced Platelets. Biomed Sci Letters. 2023b. 29: 184-189.
  17. Menshikov MYU, Ivanova K, Schaefer M, Drummer C, Gerzer R. Influence of the cGMP analog 8-PCPT-cGMP on agonist-induced increases in cytosolic ionized Ca2+ and on aggregation of human platelets. Eur J Pharmacol. 1993. 245: 281-284. https://doi.org/10.1016/0922-4106(93)90108-L
  18. 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
  19. Nishikawa M, Tanaka T, Hidaka H. Ca2+-calmodulin-dependent phosphorylation and platelet secretion. Nature. 1980. 287: 863-865. https://doi.org/10.1038/287863a0
  20. 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
  21. Peng T, Li S, Liu L, Yang C, Farhan M, Chen L, Su Q, Zheng W. Artemisinin attenuated ischemic stroke induced cell apoptosis through activation of ERK1/2/CREB/BCL-2 signaling pathway in vitro and in vivo. Int J Biol Sci. 2022. 18: 4578-4594. https://doi.org/10.7150/ijbs.69892
  22. Patrono C. Aspirin: new cardiovascular uses for an old drug. Am J Med. 2001. 110: S62-S65.
  23. 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
  24. 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
  25. 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
  26. 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
  27. 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
  28. Sudo T, Ito H, Kimura Y. Phosphorylation of the vasodilator-stimulated phosphoprotein (VASP) by the anti-platelet drug, cilostazol, in platelets. Platelets. 2003. 14: 381-390. https://doi.org/10.1080/09537100310001598819
  29. Wang J, Xu C, Wong YK, Li Y, Liao F, Jiang T, Tu Y. Artemisinin, the Magic Drug Discovered from Traditional Chinese Medicine. Engineering. 2019. 5: 32-39. https://doi.org/10.1016/j.eng.2018.11.011
  30. Wong YK, Xu C, Kalesh KA, He Y, Lin Q, Wong WSF. Artemisinin as an anticancer drug: Recent advances in target profiling and mechanisms of action. Med Res Rev. 2017. 37: 1492-1517. https://doi.org/10.1002/med.21446
  31. Xu G, Huang YL, Li PL, Guo HM, Han XP. Neuroprotective effects of artemisinin against isoflurane-induced cognitive impairments and neuronal cell death involve JNK/ERK1/2 signalling and improved hippocampal histone acetylation in neonatal rats. J Pharm Pharmacol. 2017. 69: 684-697. https://doi.org/10.1111/jphp.12704
  32. Yao Y, Guo Q, Cao Y, Qiu Y, Tan R, Yu Z. Artemisinin derivatives inactivate cancer-associated fibroblasts through sup-pressing TGF-β signaling in breast cancer. J Exp Clin Cancer Res. 2018. 37: 282.
  33. Yoon SS, Kwon HW, Shin JH, Rhee MH, Park CE, Lee DH. Antithrombotic effects of artesunate through regulation of cAMP and PI3K/MAPK pathway on human platelets. Int J Mol Sci. 2022. 23: 1586.
  34. Zeng Z, Xu J, Zheng W. Artemisinin protects PC12 cells against beta-amyloid-induced apoptosis through activation of the ERK1/2 signaling pathway. Redox Biol. 2017. 12: 625-633. https://doi.org/10.1016/j.redox.2017.04.003
  35. Zhao X, Fang J, Li S, Gaur U, Xing X, Wang H. Artemisinin Attenuated Hydrogen Peroxide (H2O2)-Induced Oxidative Injury in SH-SY5Y and Hippocampal Neurons via the Activation of AMPK Pathway. Int J Mol Sci. 2019. 20: 2680.