DOI QR코드

DOI QR Code

Cordycepin (3'-deoxyadenosine) Has an Anti-platelet Effect by Regulating the cGMP-Associated Pathway of Human Platelet Activation

  • Cho, Hyun-Jeong (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, and Regional Research Center, Inje University) ;
  • Rhee, Man-Hee (Department of Physiology, College of Veterinary Medicine, Kyungpook National University) ;
  • Cho, Jae-Youl (School of Bioscience and Biotechnology, Kangwon National University) ;
  • Kim, Hyeong-Soo (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, and Regional Research Center, Inje University) ;
  • Ok, Woo-Jeong (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, and Regional Research Center, Inje University) ;
  • Kang, Hee-Jin (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, and Regional Research Center, Inje University) ;
  • Park, Hwa-Jin (Department of Biomedical Laboratory Science, College of Biomedical Science and Engineering, and Regional Research Center, Inje University)
  • Published : 2007.09.30

Abstract

Cordycepin (3'-deoxyadenosine), which comes from Cordyceps militaris, the Chinese medicinal fungal genus Cordyceps, is used in the treatment of various diseases such as cancer and chronic inflammation. We recently reported that cordycepin has a novel antiplatelet effect through the down regulation of $[Ca^{2+}]_{i}$ and the elevation of cGMP/cAMP production. In this study, we further investigated the effect of cordycepin on collagen-induced platelet aggregation in the presence of cGMP-dependent protein kinase (PKG)- or cAMP-dependent protein kinase (PKA)-inhibitor. PKG inhibitor Rp-8-pCPT-cGMPS potentiated the collagen-induced platelet aggregation, but PKA inhibitor Rp-8-Br-cAMPS did not. However, both Rp-8-pCPT-cGMPS and Rp-8-Br-cAMPS reduced inhibition by cordycepin of collagen-induced platelet aggregation. Moreover, cordycepin inhibited $Ca^{2+}-dependent$ phosphorylation of both 47 kDa- and 20 kDa-protein in the presence of both PKG inhibitor and PKA inhibitor. Taken altogether, these results suggest that the inhibitory effect of cordycepin on collagen-induced platelet aggregation is associated with cGMP/PKG- and cAMP/PKA-pathways, and thus cordycepin may be an efficacious intervention against platelet aggregation-mediated thrombotic disease.

Keywords

References

  1. Schwartz SM, Heinmark RL, Majesky MW. 1990. Developmental mechanisms underlying pathology of arteries. Physiol Rev 70: 1177-1209 https://doi.org/10.1152/physrev.1990.70.4.1177
  2. Cattaneo M, Tenconi PM, Lecchi A, Mannucci PM. 1991. In vitro effects of picotamide on human platelet aggregation, the release reaction and thromboxane $B_2$ production. Thromb Res 62: 717-724 https://doi.org/10.1016/0049-3848(91)90375-7
  3. Wonerow P, Obergfell A, Wilde JI, Bobe R, Asazuma N, Brdicka T, Leo A, Schraven B, Horejsi V, Shattil SJ, Watson SP. 2002. Differential role of glycolipid-enriched membrane domains in glycoprotein VI- and integrin- mediated phospholipase C gamma 2 regulation in platelets. Biochem J 364: 755-765 https://doi.org/10.1042/BJ20020128
  4. Berridge MJ, Irvine RF. 1989. Inositol phosphates and cell signalling. Nature 341: 197-205 https://doi.org/10.1038/341197a0
  5. Kaibuchi K, Sano K, Hoshijima M, Takai Y, Nishizuka Y. 1982. Phosphatidylinositol turnover in platelet activation; calcium mobilization and protein phosphorylation. Cell Calcium 3: 323-335 https://doi.org/10.1016/0143-4160(82)90020-3
  6. Nishikawa M, Tanaka T, Hidaka H. 1980. $Ca^{2+}$-calmodulin-dependent phosphorylation and platelet secretion. Nature 287: 863-865 https://doi.org/10.1038/287863a0
  7. Menshikov MYu, Ivanova K, Schaefer M, Drummer C, Gerzer R. 1993. Influence of the cGMP analog 8-PCPT-cGMP on agonist-induced increases in cytosolic ionized $Ca^{2+}$ and on aggregation of human platelets. Eur J Pharmacol 245: 281-284 https://doi.org/10.1016/0922-4106(93)90108-L
  8. Pasqui AL, Capecci PL, Ceccatelli L, Mazza S, Gistri A, Laghi Pasini F, Di Perry T. 1991. Nitroprusside in vitro inhibits platelet aggregation and intracellular calcium translocation. Effect of haemoglobin. Thromb Res 61: 113- 122 https://doi.org/10.1016/0049-3848(91)90238-R
  9. Rodomski MW, Palmer RMJ, Monacade S. 1990. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 87: 5193- 5197
  10. Cuningham KG, Hutchinson SA, Manson W, Spring FS. 1951. Cordycepin, a metabolic product from culture of ordyceps militaris (Linn) Link. Part Ⅰ. Isolation and characterization. J Chem Soc 2: 2299-2302
  11. Ng TB, Wang HX. 2005. Pharmacological actions of Cordyceps, a prized folk medicine. J Pharm Pharmacol 57: 1509-1519 https://doi.org/10.1211/jpp.57.12.0001
  12. Hubbell HR, Pequignot EC, Wllis DH, Lee C, Suhadolnik RJ. 1985. Differential antiproliferative actons of 2', 5'-oligo A trimer core and its cordycepin analogue on human tumor cells. Int J Cancer 36: 389-394 https://doi.org/10.1002/ijc.1985.36.3.389
  13. Won SY, Park EH. 2005. Anti-inflammatory and related pharmacological activities of cultured mycelia and fruiting bodies of Cordyceps militaris. J Ethnopharmacol 96: 555-561 https://doi.org/10.1016/j.jep.2004.10.009
  14. Son DJ, Kim YM, Chung NH, Lee HS. 2005. Antiplatelet activity of Thujopsis dolabrata var. hondai-derived component against platelet aggregation. J Microbiol Biotechnol 15: 425-427
  15. Yang BK, Ha JY, Jong SC, Das S, Yun JW, Lee YS, Choi JW, Song CH. 2000. Production of exopolymers by submerged mycelial culture of Cordyceps militaris and its hypolipidemic effect. J Microbiol Biotechnol 10: 784-788
  16. Yu KW, Suh HJ, Bae SH, Lee CS, Kim SH, Yoon CS. 2001. Chemical properties and physiological activities of stromata of Cordyceps militaris. J Microbiol Biotechnol 11: 266-274
  17. Jang EK, Azzam JE, Dickinson NT, Davidson MM, Haslam RJ. 2002. Roles for both cyclic GMP and cyclic AMP in the inhibition of collagen-induced platelet aggregation by nitroprusside. Br J Haematol 117: 664-675 https://doi.org/10.1046/j.1365-2141.2002.03479.x
  18. Glazer RI, Kuo JF. 1977. Inhibitory effects of cordycepin on cyclic nucleotide-dependent and cyclic nucleotide-independent protein kinase. Biochem Pharmacol 26: 1287- 1290 https://doi.org/10.1016/0006-2952(77)90085-5
  19. Laemmli UK. 1970. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227: 680-685 https://doi.org/10.1038/227680a0
  20. Cho HJ, Ham HS, Lee TK, Jung YJ, Choi SA, Kang HC, Park HJ. 2004. Inhibitory effect of cordycepin on human platelet aggregation. J Biomed Lab Sci 10: 1-8
  21. Cho HJ, Cho JY, Rhee MH, Park HJ. 2007a. Cordycepin (3'-deoxyadenosine) inhibits human platelets aggregation in a cyclic AMP- and cyclic GMP-dependent manner. Eur J Pharmacol 558: 43-51 https://doi.org/10.1016/j.ejphar.2006.11.073
  22. Cho HJ, Cho JY, Rhee MH, Kim HS, Lee HS, Park HJ. 2007b. Inhibitory effects of platelet aggregation indyced by thapsigargin. J Microbiol Biotechnol 17: 1334-1138
  23. Butt E, Eigenthaler M, Genieser HG. 1994. Rp-8-pCPT, a novel cGMP-dependent protein kinase inhibitor. Eur J pharmacol 269: 265-268 https://doi.org/10.1016/0922-4106(94)90095-7
  24. Li Z, Ajdic J, Eigenthaler M, Du X. 2003. A predominant role for cAMP-dependent protein kinase in the cGMP-induced phosphorylation of vasodilator-stimulated phosphoprotein and platelet inhibition in humans. Blood 101: 4423-4429 https://doi.org/10.1182/blood-2002-10-3210
  25. Yuasa K, Michibata H, Omori K, Yanaka N. 2000. Identification of a conserved residue responsible for the autoinhibition of cGMP-dependent protein kinase I$\alpha$ and $\beta$. FEBS Letters 466: 175-178 https://doi.org/10.1016/S0014-5793(99)01786-X
  26. Massberg S, Sausbier M, Klatt P, Bauer M, Pfeifer A, Siess W, Fassler R, Ruth P, Krombach F, Hofmann F. 1999. Increased adhension and aggregation of platelets lacking cyclic guanosine 3',5'-monophosphate kinase I. J Exp Med 189: 1255-1263 https://doi.org/10.1084/jem.189.8.1255
  27. Schwarz UR, Walter U, Eigenthaler M. 2001. Taming platelets with cyclic nucleotides. Biochem Pharmacy 62: 1153-1161 https://doi.org/10.1016/S0006-2952(01)00760-2
  28. Munzel T, Feil R, Mulsch A, Lohmann SM, Hofmann F, Walter U. 2003. Physiology and pathophysiology of vascular signaling controlled by cyclic guanosine 3',5'-cyclic monophosphate-dependent protein kinase. Circulation 108: 2172-2183 https://doi.org/10.1161/01.CIR.0000094403.78467.C3
  29. Cho HJ, Cho JY, Rhee MH, Lim CR, Park HJ. 2006. Cordycepin (3'-deoxyadenosine) inhibits human platelet aggregation induced by U46619, a $TXA_2$ analogue. J Pharm Pharmacol 58: 1677-1682 https://doi.org/10.1211/jpp.58.12.0016
  30. Charo IF, Feinman RD, Detwiler TC. 1977. Interrelations of platelet aggregation and secretion. J Clin Invest 60: 866-873 https://doi.org/10.1172/JCI108841.