Biotechnology and Bioprocess Engineering

, Volume 23, Issue 6, pp 641–648 | Cite as

Caffeic Acid Diminishes the Production and Release of Thrombogenic Molecules in Human Platelets

  • Gi Suk Nam
  • Kyung-Soo Nam
  • Hwa-Jin ParkEmail author
Research Paper


Caffeic acid (CA) is a well-known to inhibit thrombogenic thromboxane A2 (TXA2) production, but there are no reports for the supply and usage of its precursor arachidonic acid (AA) and the release of serotonin, another thrombogenic molecule. In this study, we investigated the effect of CA on the phosphorylation of AA supply enzymes [cytosolic phospholipase A (cPLA), and phospholipase Cγ2 (PLCγ2)] and AA utilization enzymes [cyclooxygenase (COX)-1, TXA2 synthase (TXAS)] in collagen-activated human platelets. p38 MAPK phosphorylation associated with TXA2 production and c-Jun NH2-terminal kinase 1 (JNK1) phosphorylation associated with serotonin release were also determined. CA inhibited collagen-induced TXA2 production in a dose-dependent manner. It acted by counteracting the phosphorylation of AA release enzyme (PLCγ2) and AA utilization enzymes (COX-1 and TXAS) without affecting p38 MAPK and cPLA in collagenactivated human platelets. CA decreased collagen-released serotonin by inhibiting JNK1 phosphorylation. Therefore, our data demonstrate that CA might protect TXA2- and serotonin-mediated thrombogenesis.


Caffeic acid thromboxane A2 serotonin cyclooxygenase-1 thromboxane A2 synthase c-Jun NH2-terminal kinase 1 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Schwartz, S. M., R. L. Heimark, and M. W. Majesky (1990) Developmental mechanisms underlying pathology of arteries. Physiol. Rev. 70: 1177–1209.CrossRefGoogle Scholar
  2. 2.
    Berridge, M. J. and R. F. Irvine (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312: 315–321.CrossRefGoogle Scholar
  3. 3.
    Jennings, L. K. (2009) Role of Platelets in Atherothrombosis. Am. J. Cardiol. 103: 4A–10A.CrossRefGoogle Scholar
  4. 4.
    Mangin, P., C. Nonne, A. Eckly, P. Ohlmann, M. Freund, B. Nieswandt, J. P. Cazenave, and F. Lanza (2003) A PLC?2–independent platelet collagen aggregation requiring functional aßsociation of GPVI and integrin a2ß1. FEBS Lett. 542: 53–59.CrossRefGoogle Scholar
  5. 5.
    Nishikawa, M., T. Tanaka, and H. Hidaka, (1980) Ca2+–calmodulin–dependent phosphorylation and platelet secretion. Nature 287: 863–865.CrossRefGoogle Scholar
  6. 6.
    Kaibuchi, K., K. Sano, M. Hoshijima, Y. Takai, and Y. Nishizuka (1982) Phosphatidylinositol turnover in platelet activation; calcium mobilization and protein phosphorylation. Cell Calcium. 3: 323–335.CrossRefGoogle Scholar
  7. 7.
    Kramer, R. M., E. F. Roberts, S. L. Um. A. G. Börsch–Haubold, S. P. Watson, M. J. Fisher, and J. A. Jakubowski (1996) p38 mitogen–activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin–stimulated platelets. J. Biol. Chem. 271: 27723–27729.CrossRefGoogle Scholar
  8. 8.
    Lee, J. S., K. R. Lee, S. Lee, H. J. Lee, H. S. Yang, J. H. Yeo, J. M. Park, B. H. Choi, and E. K. Hong (2017) Polysaccharides isolated from liquid culture broth of Inonotus obliquus inhibit the invasion of human non–small cell lung carcinoma cells. Biotechnol. Bioproc. Eng. 22: 45–51.CrossRefGoogle Scholar
  9. 9.
    Lee, K. S., D. H. Lee, Y. S. Kwon, S. Y. Chun, and K. S. Nam (2014) Deep–sea water inhibits metastatic potential in HT–29 human colorectal adenocarcinomas via MAPK/NF–?B signaling pathway. Biotechnol. Bioproc. Eng. 19: 733–739.CrossRefGoogle Scholar
  10. 10.
    FitzGerald, G. A. (1991) Mechanisms of platelet activation: thromboxane A2 as an amplifying signal for other agonists. Am. J. Cardiol. 68: 11B–15B.CrossRefGoogle Scholar
  11. 11.
    Ruggeri, Z. M. (2002) Platelets in atherothrombosis. Nat. Med. 8: 1227–1234.CrossRefGoogle Scholar
  12. 12.
    Armstrong, P. C., N. S. Kirkby, Z. N. Zain, M. Emerson, J. A. Mitchell, and T. D. Warner (2011) Thrombosis is reduced by inhibition of COX–1, but unaffected by inhibition of COX–2, in an acute model of platelet activation in the mouse. PLoS One 6: e20062.CrossRefGoogle Scholar
  13. 13.
    Ichikawa, K., S. Tazawa, S. Hamano, M. Kojima, and S. Hiraku (1999) Effect of ozagrel on locomotor and motor coordination after transient cerebral ischemia in experimental animal models. Pharmacology 59: 257–265.CrossRefGoogle Scholar
  14. 14.
    Malhotra, S., Y. P. Sharma, A. Grover, S. Majumdar, S. M. Hanif, V. K. Bhargava, A. Bhatnagar, and P. Pandhi (2003) Effect of different aspirin doses on platelet aggregation in patients with stable coronary artery disease. Intern. Med. J. 33: 350–354.CrossRefGoogle Scholar
  15. 15.
    Pulcinelli, F. M., P. Pignatelli, A. Celestini, S. Riondino, P. P. Gazzaniga, and F. Violi (2004) Inhibition of platelet aggregation by aspirin progressively decreases in long–term treated patients. J. Am. Coll. Cardiol. 43: 979–984.CrossRefGoogle Scholar
  16. 16.
    Lee, D. H., H. H. Kim, H. J. Cho, J. S. Bae, Y. B. Yu, and H. J. Park (2014) Antiplatelet effects of caffeic acid due to Ca2+ mobilization–inhibition via cAMP–dependent inositol–1, 4, 5–trisphosphate receptor phosphorylation. J. Atheroscler. Thromb. 21: 23–37.CrossRefGoogle Scholar
  17. 17.
    Lu, Y., Q. Li, Y. Y. Liu, K. Sun, J. Y. Fan, C. S. Wang, and J. Y. Han (2015) Inhibitory effect of caffeic acid on ADP–induced thrombus formation and platelet activation involves mitogenactivated protein kinases. Sci. Rep. 5: 13824.CrossRefGoogle Scholar
  18. 18.
    Kauskot, A., F. Adam, A. Mazharian, N. Ajzenberg, E. Berrou, A. Bonnefoy, J. P. Rosa, M. F. Hoylaerts, and M. Bryckaert (2007) Involvement of the mitogen–activated protein kinase c–Jun NH2–terminal kinase 1 in thrombus formation. J. Biol. Chem 282: 31990–31999.CrossRefGoogle Scholar
  19. 19.
    Adam, F., A. Kauskot, J. P. Rosa, and M. Bryckaert (2008) Mitogen–activated protein kinases in hemostasis and thrombosis. J. Thromb. Haemost. 6: 2007–2016.CrossRefGoogle Scholar
  20. 20.
    Adam, F., A. Kauskot, P. Nurden, E. Sulpice, M. F. Hoylaerts, R. J. Davis, J. P. Rosa, and M. Bryckaert (2010) Platelet JNK1 is involved in secretion and thrombus formation. Blood 115: 4083–4092.CrossRefGoogle Scholar
  21. 21.
    Jackson, E. C. G., G. Ortar, and A. McNicol (2013) The effects of an inhibitor of diglyceride lipase on collagen–induced platelet activation. J. Pharmacol. Exp. Ther. 347: 582–588.CrossRefGoogle Scholar
  22. 22.
    Shin, J. H., H. W. Kwon, M. H. Rhee, and H. J. Park (2018) Inhibitory effects of thromboxane A2 generation by ginsenoside Ro due to attenuation of cytosolic phospholipase A2 phosphorylation and arachidonic acid release. J. Ginseng Res. Scholar
  23. 23.
    Chen, T. G., J. J. Lee, K. H. Lin, C. H. Shen, D. S. Chou, and J. R. Sheu (2007) Antiplatelet activity of caffeic acid phenethyl ester is mediated through a cyclic GMP–dependent pathway in human platelets. Chin. J. Physiol. 50: 121–126.Google Scholar
  24. 24.
    Park, J. B. (2009) 5–Caffeoylquinic acid and caffeic acid orally administered suppress P–selectin expression on mouse platelets. J. Nutr. Biochem. 20: 800–805.CrossRefGoogle Scholar

Copyright information

© The Korean Society for Biotechnology and Bioengineering and Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biomedical Laboratory Science, College of Healthcare Medical Science EngineeringInje UniversityGimhaeKorea
  2. 2.Department of Pharmacology and Intractable Disease Research Center, School of MedicineDongguk UniversityGyeongjuKorea

Personalised recommendations