Biomolecules & Therapeutics

The Korean Society of Applied Pharmacology (한국응용약물학회)
권호 표지
DOI QR코드

DOI QR Code

Enhancement of Platelet Aggregation by Ursolic Acid and Oleanolic Acid

  • Kim, Mikyung (College of Pharmacy, Dongguk University) ;
  • Han, Chang-Ho (Department of Internal Medicine, College of Korean Medicine, Dongguk University) ;
  • Lee, Moo-Yeol (College of Pharmacy, Dongguk University)
  • Received : 2014.01.24
  • Accepted : 2014.03.24
  • Published : 2014.05.31
Download PDF
⟨ Previous Next ⟩

Abstract

The pentacyclic triterpenoid ursolic acid (UA) and its isomer oleanolic acid (OA) are ubiquitous in food and plant medicine, and thus are easily exposed to the population through natural contact or intentional use. Although they have diverse health benefits, reported cardiovascular protective activity is contentious. In this study, the effect of UA and OA on platelet aggregation was examined on the basis that alteration of platelet activity is a potential process contributing to cardiovascular events. Treatment of UA enhanced platelet aggregation induced by thrombin or ADP, which was concentration-dependent in a range of $5-50{\mu}M$. Quite comparable results were obtained with OA, in which OA-treated platelets also exhibited an exaggerated response to either thrombin or ADP. UA treatment potentiated aggregation of whole blood, while OA failed to increase aggregation by thrombin. UA and OA did not affect plasma coagulation assessed by measuring prothrombin time and activated partial thromboplastin time. These results indicate that both UA and OA are capable of making platelets susceptible to aggregatory stimuli, and platelets rather than clotting factors are the primary target of them in proaggregatory activity. These compounds need to be used with caution, especially in the population with a predisposition to cardiovascular events.

Keywords

References

  1. Aguirre-Crespo, F., Vergara-Galicia, J., Villalobos-Molina, R., Javier Lopez-Guerrero, J., Navarrete-Vazquez, G. and Estrada-Soto, S. (2006) Ursolic acid mediates the vasorelaxant activity of Lepechinia caulescens via NO release in isolated rat thoracic aorta. Life Sci. 79, 1062-1068. https://doi.org/10.1016/j.lfs.2006.03.006
  2. Allouche, Y., Beltran, G., Gaforio, J. J., Uceda, M. and Mesa, M. D. (2010) Antioxidant and antiatherogenic activities of pentacyclic triterpenic diols and acids. Food Chem. Toxicol. 48, 2885-2890. https://doi.org/10.1016/j.fct.2010.07.022
  3. Andrikopoulos, N. K., Kaliora, A. C., Assimopoulou, A. N. and Papageorgiou, V. P. (2002) Inhibitory activity of minor polyphenolic and nonpolyphenolic constituents of olive oil against in vitro low-density lipoprotein oxidation. J. Med. Food 5, 1-7. https://doi.org/10.1089/109662002753723160
  4. Babalola, I. T., Shode, F. O., Adelakun, E. A., Opoku, A. R. and Mosa, R. A. (2013) Platelet-aggregation inhibitory activity of oleanolic acid, ursolic acid, betulinic acid, and maslinic acid. J. Pharmacogn. Phytochem. 1, 54-60.
  5. Chen, Q., Luo, S., Zhang, Y. and Chen, Z. (2011) Development of a liquid chromatography-mass spectrometry method for the determination of ursolic acid in rat plasma and tissue: application to the pharmacokinetic and tissue distribution study. Anal. Bioanal. Chem. 399, 2877-2884. https://doi.org/10.1007/s00216-011-4651-x
  6. Dyszkiewicz-Korpanty, A., Olteanu, H., Frenkel, E. P. and Sarode, R. (2007) Clopidogrel anti-platelet effect: an evaluation by optical aggregometry, impedance aggregometry, and the platelet function analyzer (PFA-100TM). Platelets 18, 491-496. https://doi.org/10.1080/09537100701280654
  7. Horiuchi, K., Shiota, S., Hatano, T., Yoshida, T., Kuroda, T. and Tsuchiya, T. (2007) Antimicrobial activity of oleanolic acid from Salvia officinalis and related compounds on vancomycin-resistant enterococci (VRE). Biol. Pharm. Bull. 30, 1147-1149. https://doi.org/10.1248/bpb.30.1147
  8. Ikeda, Y., Murakami, A. and Ohigashi, H. (2008) Ursolic acid: an antiand pro-inflammatory triterpenoid. Mol. Nutr. Food Res. 52, 26-42. https://doi.org/10.1002/mnfr.200700389
  9. Ingerman-Wojenski, C., Smith, J. B. and Silver, M. J. (1983) Evaluation of electrical aggregometry: comparison with optical aggregometry, secretion of ATP, and accumulation of radiolabeled platelets. J. Lab. Clin. Med. 101, 44-52.
  10. Jager, S., Trojan, H., Kopp, T., Laszczyk, M. N. and Scheffler, A. (2009) Pentacyclic triterpene distribution in various plants - rich sources for a new group of multi-potent plant extracts. Molecules 14, 2016-2031. https://doi.org/10.3390/molecules14062016
  11. Jarvis, G. E. (2004) Platelet aggregation in whole blood - Impedance and particle counting methods. In Platelets and megakaryocytes (Gibbins, J. M. and Mahaut-Smith M. P.), pp. 77-87. Humana Press, Totowa, N.J.
  12. Jeong, D. W., Kim, Y. H., Kim, H. H., Ji, H. Y., Yoo, S. D., Choi, W. R., Lee, S. M., Han, C. K. and Lee, H. S. (2007) Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats. Biopharm. Drug Dispos. 28, 51-57. https://doi.org/10.1002/bdd.530
  13. Jin, I. J., Ko, Y. I., Kim, Y. M. and Han, S. K. (1997) Solubilization of oleanolic acid and ursolic acid by cosolvency. Arch. Pharm. Res. 20, 269-274. https://doi.org/10.1007/BF02976156
  14. Jin, J. L., Lee, S., Lee, Y. Y., Kim, J. M., Heo, J. E. and Yun-Choi, H. S. (2004a) Platelet anti-aggregating triterpenoids from the leaves of Acanthopanax senticosus and the fruits of A. sessiliflorus. Planta Med. 70, 564-566. https://doi.org/10.1055/s-2004-827159
  15. Jin, J. L., Lee, Y. Y., Heo, J. E., Lee, S., Kim, J. M. and Yun-Choi, H. S. (2004b) Anti-platelet pentacyclic triterpenoids from leaves of Campsis grandiflora. Arch. Pharm. Res. 27, 376-380. https://doi.org/10.1007/BF02980076
  16. Lee, J. J., Jin, Y. R., Lim, Y., Yu, J. Y., Kim, T. J., Yoo, H. S., Shin, H. S. and Yun, Y. P. (2007) Oleanolic acid, a pentacyclic triterpenoid, induces rabbit platelet aggregation through a phospholipase C-calcium dependent signaling pathway. Arch. Pharm. Res. 30, 210-214. https://doi.org/10.1007/BF02977696
  17. Lee, M. H. and Han, Y. N. (2003) A new in vitro tissue factor inhibitory triterpene from the fruits of Chaenomeles sinensis. Planta Med. 69, 327-331. https://doi.org/10.1055/s-2003-38884
  18. Lee, W., Yang, E. J., Ku, S. K., Song, K. S. and Bae, J. S. (2012) Anticoagulant activities of oleanolic acid via inhibition of tissue factor expressions. BMB Rep. 45, 390-395. https://doi.org/10.5483/BMBRep.2012.45.7.065
  19. Liu, J. (1995) Pharmacology of oleanolic acid and ursolic acid. J. Ethnopharmacol. 49, 57-68. https://doi.org/10.1016/0378-8741(95)90032-2
  20. Liu, J. (2005) Oleanolic acid and ursolic acid: research perspectives. J. Ethnopharmacol. 100, 92-94. https://doi.org/10.1016/j.jep.2005.05.024
  21. Liu, Y., Oh, S. J., Chang, K. H., Kim, Y. G. and Lee, M. Y. (2013) Antiplatelet effect of AMP-activated protein kinase activator and its potentiation by the phosphodiesterase inhibitor dipyridamole. Biochem. Pharmacol. 86, 914-925. https://doi.org/10.1016/j.bcp.2013.07.009
  22. Messner, B., Zeller, I., Ploner, C., Frotschnig, S., Ringer, T., Steinacher- Nigisch, A., Ritsch, A., Laufer, G., Huck, C. and Bernhard, D. (2011) Ursolic acid causes DNA-damage, p53-mediated, mitochondria- and caspase-dependent human endothelial cell apoptosis, and accelerates atherosclerotic plaque formation in vivo. Atherosclerosis 219, 402-408. https://doi.org/10.1016/j.atherosclerosis.2011.05.025
  23. Michelson, A. D. (2010) Antiplatelet therapies for the treatment of cardiovascular disease. Nat. Rev. Drug Discov. 9, 154-169. https://doi.org/10.1038/nrd2957
  24. Offermanns, S. (2006) Activation of platelet function through G proteincoupled receptors. Circ. Res. 99, 1293-1304. https://doi.org/10.1161/01.RES.0000251742.71301.16
  25. Oh, S. J., Kim, H., Liu, Y., Han, H. K., Kwon, K., Chang, K. H., Park, K., Kim, Y., Shim, K., An, S. S. and Lee, M. Y. (2014) Incompatibility of silver nanoparticles with lactate dehydrogenase leakage assay for cellular viability test is attributed to protein binding and reactive oxygen species generation. Toxicol. Lett. 225, 422-432. https://doi.org/10.1016/j.toxlet.2014.01.015
  26. Pollier, J. and Goossens, A. (2012) Oleanolic acid. Phytochemistry 77, 10-15. https://doi.org/10.1016/j.phytochem.2011.12.022
  27. Radhiga, T., Rajamanickam, C., Senthil, S. and Pugalendi, K. V. (2012) Effect of ursolic acid on cardiac marker enzymes, lipid profile and macroscopic enzyme mapping assay in isoproterenol-induced myocardial ischemic rats. Food Chem. Toxicol. 50, 3971-3977. https://doi.org/10.1016/j.fct.2012.07.067
  28. Rodriguez-Rodriguez, R., Stankevicius, E., Herrera, M., Ostergaard, L., Andersen, M. R., Ruiz-Gutierrez, V. and Simonsen, U. (2008) Oleanolic acid induces relaxation and calcium-independent release of endothelium-derived nitric oxide. Br. J. Pharmacol. 155, 535-546.
  29. Sarkar, D., Srimany, A. and Pradeep, T. (2012) Rapid identification of molecular changes in tulsi (Ocimum sanctum Linn) upon ageing using leaf spray ionization mass spectrometry. Analyst 137, 4559-4563. https://doi.org/10.1039/c2an35655d
  30. Somova, L., Shode, F. and Mipando, M. (2004) Cardiotonic and antidysrhythmic effects of oleanolic and ursolic acids, methyl maslinate and uvaol. Phytomedicine 11, 121-129. https://doi.org/10.1078/0944-7113-00329
  31. Somova, L. O., Nadar, A., Rammanan, P. and Shode, F. O. (2003) Cardiovascular, antihyperlipidemic and antioxidant effects of oleanolic and ursolic acids in experimental hypertension. Phytomedicine 10, 115-121. https://doi.org/10.1078/094471103321659807
  32. Song, M., Hang, T. J., Wang, Y., Jiang, L., Wu, X. L., Zhang, Z., Shen, J. and Zhang, Y. (2006) Determination of oleanolic acid in human plasma and study of its pharmacokinetics in Chinese healthy male volunteers by HPLC tandem mass spectrometry. J. Pharm. Biomed. Anal. 40, 190-196. https://doi.org/10.1016/j.jpba.2005.06.034
  33. Ullevig, S. L., Zhao, Q., Zamora, D. and Asmis, R. (2011) Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis. Atherosclerosis 219, 409-416. https://doi.org/10.1016/j.atherosclerosis.2011.06.013
  34. Wang, J., Ma, H., Zhang, X., He, L., Wu, J., Gao, X., Ren, J. and Li, J. (2009) A novel AMPK activator from Chinese herb medicine and ischemia phosphorylate the cardiac transcription factor FOXO3. Int. J. Physiol. Pathophysiol. Pharmacol. 1, 116-126.
  35. Xia, E.-Q., Wang, B. W., Xu, X. R., Zhu, L., Song, Y. and Li, H. B. (2011a) Microwave-assisted extraction of oleanolic acid and ursolic acid from Ligustrum lucidum ait. Int. J. Mol. Sci. 12, 5319-5329. https://doi.org/10.3390/ijms12085319
  36. Xia, Y., Wei, G., Si, D. and Liu, C. (2011b) Quantitation of ursolic acid in human plasma by ultra performance liquid chromatography tandem mass spectrometry and its pharmacokinetic study. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 879, 219-224. https://doi.org/10.1016/j.jchromb.2010.11.037
  37. Zha, X. Z., Xie, X. M., Lu, M. H., Zhou, A. and Liu, X. H. (2010) Analysis of fruits from ten chinese medicinal herbs containing oleanolic acid and ursolic acid by HPLC. Chin. J. Exp. Tradit. Med. Formulae. 18, 019.

Cited by

  1. Thrombin Maybe Plays an Important Role in MK Differentiation into Platelets vol.2016, 2016, https://doi.org/10.1155/2016/9313269
  2. Synergistic Effect of Oleanolic Acid on Aminoglycoside Antibiotics against Acinetobacter baumannii vol.10, pp.9, 2015, https://doi.org/10.1371/journal.pone.0137751
  3. Anti-platelet and anti-thrombotic effect of a traditional herbal medicine Kyung-Ok-Ko vol.178, 2016, https://doi.org/10.1016/j.jep.2015.11.040
  4. Rosemary (Rosmarinus officinalis) as a potential therapeutic plant in metabolic syndrome: a review vol.389, pp.9, 2016, https://doi.org/10.1007/s00210-016-1256-0
  5. Deconvoluting the Dual Antiplatelet Activity of a Plant Extract vol.64, pp.22, 2016, https://doi.org/10.1021/acs.jafc.6b00544
  6. Ursolic Acid—A Pentacyclic Triterpenoid with a Wide Spectrum of Pharmacological Activities vol.20, pp.12, 2015, https://doi.org/10.3390/molecules201119721
  7. Studies on New Activities of Enantiomers of 2-(2-Hydroxypropanamido) Benzoic Acid: Antiplatelet Aggregation and Antithrombosis vol.12, pp.1, 2017, https://doi.org/10.1371/journal.pone.0170334
  8. Synthesis of Water-soluble, Polyester-based Dendrimer Prodrugs for Exploiting Therapeutic Properties of Two Triterpenoid Acids vol.36, pp.9, 2018, https://doi.org/10.1007/s10118-018-2124-9
  9. Untargeted fecal metabolomics revealed biochemical mechanisms of the blood lipid-lowering effect of koumiss treatment in patients with hyperlipidemia vol.78, pp.None, 2014, https://doi.org/10.1016/j.jff.2021.104355