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Inflammation

, Volume 37, Issue 5, pp 1424–1431 | Cite as

Inhibitory Effects of Rutin on the Endothelial Protein C Receptor Shedding In Vitro and In Vivo

  • Sae-Kwang Ku
  • In-Chul Lee
  • Min-Su Han
  • Jong-Sup Bae
Article

Abstract

Endothelial cell protein C receptor (EPCR) has important functions in regulation of coagulation and inflammation. EPCR shedding from the cell surface is mediated by tumor necrosis factor-α converting enzyme (TACE). Rutin is one of the major flavonoids from the buckwheat plant Fagopyrum tataricum. In this study, we investigated the effects of rutin on phorbol-12-myristate 13-acetate (PMA), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and on cecal ligation and puncture (CLP)-mediated EPCR shedding. We used a CLP model because this model more closely resembles human sepsis. Data showed rutin was a potent inhibitor of PMA, TNF-α, IL-1β, and CLP-induced EPCR shedding by suppression of TACE expression. Treatment with rutin resulted in a decrease of PMA-stimulated phosphorylation of p38, extracellular regulated kinases 1/2, and c-Jun N-terminal kinase. These results suggest the potential application of rutin for treatment of PMA and CLP-mediated EPCR shedding.

KEY WORDS

rutin EPCR shedding PMA CLP 

Notes

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF) funded by the Korea government [MSIP] (Grant no. 2013–067053).

Conflict of Interest

None.

References

  1. 1.
    Fukudome, K., and C.T. Esmon. 1994. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. Journal of Biological Chemistry 269: 26486–26491.PubMedGoogle Scholar
  2. 2.
    Fukudome, K., S. Kurosawa, D.J. Stearns-Kurosawa, X. He, A.R. Rezaie, and C.T. Esmon. 1996. The endothelial cell protein C receptor. Cell surface expression and direct ligand binding by the soluble receptor. Journal of Biological Chemistry 271: 17491–17498.PubMedCrossRefGoogle Scholar
  3. 3.
    Mosnier, L.O., B.V. Zlokovic, and J.H. Griffin. 2007. The cytoprotective protein C pathway. Blood 109: 3161–3172.PubMedCrossRefGoogle Scholar
  4. 4.
    Kurosawa, S., D.J. Stearns-Kurosawa, C.W. Carson, A. D'Angelo, P. Della Valle, and C.T. Esmon. 1998. Plasma levels of endothelial cell protein C receptor are elevated in patients with sepsis and systemic lupus erythematosus: lack of correlation with thrombomodulin suggests involvement of different pathological processes. Blood 91: 725–727.PubMedGoogle Scholar
  5. 5.
    Kurosawa, S., D.J. Stearns-Kurosawa, N. Hidari, and C.T. Esmon. 1997. Identification of functional endothelial protein C receptor in human plasma. Journal of Clinical Investigation 100: 411–418.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Liaw, P.C., P.F. Neuenschwander, M.D. Smirnov, and C.T. Esmon. 2000. Mechanisms by which soluble endothelial cell protein C receptor modulates protein C and activated protein C function. Journal of Biological Chemistry 275: 5447–5452.PubMedCrossRefGoogle Scholar
  7. 7.
    Stearns-Kurosawa, D.J., K. Swindle, A. D'Angelo, et al. 2002. Plasma levels of endothelial protein C receptor respond to anticoagulant treatment. Blood 99: 526–530.PubMedCrossRefGoogle Scholar
  8. 8.
    Xu, J., D. Qu, N.L. Esmon, and C.T. Esmon. 2000. Metalloproteolytic release of endothelial cell protein C receptor. Journal of Biological Chemistry 275: 6038–6044.PubMedCrossRefGoogle Scholar
  9. 9.
    Wang, L., J.A. Bastarache, N. Wickersham, X. Fang, M.A. Matthay, and L.B. Ware. 2007. Novel role of the human alveolar epithelium in regulating intra-alveolar coagulation. American Journal of Respiratory Cell and Molecular Biology 36: 497–503.PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Perez-Casal, M., C. Downey, K. Fukudome, G. Marx, and C.H. Toh. 2005. Activated protein C induces the release of microparticle-associated endothelial protein C receptor. Blood 105: 1515–1522.PubMedCrossRefGoogle Scholar
  11. 11.
    Scaldaferri, F., M. Sans, S. Vetrano, et al. 2007. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. Journal of Clinical Investigation 117: 1951–1960.PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Aggarwal, B.B., H. Ichikawa, P. Garodia, et al. 2006. From traditional Ayurvedic medicine to modern medicine: identification of therapeutic targets for suppression of inflammation and cancer. Expert Opinion on Therapeutic Targets 10: 87–118.PubMedCrossRefGoogle Scholar
  13. 13.
    Ushida, Y., T. Matsui, M. Tanaka, et al. 2008. Endothelium-dependent vasorelaxation effect of rutin-free tartary buckwheat extract in isolated rat thoracic aorta. Journal of Nutrition and Biochemistry 19: 700–707.CrossRefGoogle Scholar
  14. 14.
    Knekt, P., J. Kumpulainen, R. Jarvinen, et al. 2002. Flavonoid intake and risk of chronic diseases. American Journal of Clinical Nutrition 76: 560–568.PubMedGoogle Scholar
  15. 15.
    Guo, R., P. Wei, and W. Liu. 2007. Combined antioxidant effects of rutin and vitamin C in Triton X-100 micelles. Journal of Pharmaceutical and Biomedical Analysis 43: 1580–1586.PubMedCrossRefGoogle Scholar
  16. 16.
    Korkmaz, A., and D. Kolankaya. 2010. Protective effect of rutin on the ischemia/reperfusion induced damage in rat kidney. Journal of Surgical Research 164: 309–315.PubMedCrossRefGoogle Scholar
  17. 17.
    Milde, J., E.F. Elstner, and J. Grassmann. 2004. Synergistic inhibition of low-density lipoprotein oxidation by rutin, gamma-terpinene, and ascorbic acid. Phytomedicine 11: 105–113.PubMedCrossRefGoogle Scholar
  18. 18.
    Lee, W., S.K. Ku, and J.S. Bae. 2012. Barrier protective effects of rutin in LPS-induced inflammation in vitro and in vivo. Food and Chemical Toxicology 50: 3048–3055.PubMedCrossRefGoogle Scholar
  19. 19.
    Borgel, D., C. Bornstain, P.H. Reitsma, et al. 2007. A comparative study of the protein C pathway in septic and nonseptic patients with organ failure. American Journal of Respiratory and Critical Care Medicine 176: 878–885.PubMedCrossRefGoogle Scholar
  20. 20.
    Bae, J.S., and A.R. Rezaie. 2011. Activated protein C inhibits high mobility group box 1 signaling in endothelial cells. Blood 118: 3952–3959.PubMedCrossRefPubMedCentralGoogle Scholar
  21. 21.
    Kim, D.C., W. Lee, and J.S. Bae. 2011. Vascular anti-inflammatory effects of curcumin on HMGB1-mediated responses in vitro. Inflammation Research 60: 1161–1168.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang, H., H. Liao, M. Ochani, et al. 2004. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Medicine 10: 1216–1221.PubMedCrossRefGoogle Scholar
  23. 23.
    Qu, D., Y. Wang, Y. Song, N.L. Esmon, and C.T. Esmon. 2006. The Ser219–Gly dimorphism of the endothelial protein C receptor contributes to the higher soluble protein levels observed in individuals with the A3 haplotype. Journal of Thrombosis and Haemostasis 4: 229–235.PubMedCrossRefGoogle Scholar
  24. 24.
    Qu, D., Y. Wang, N.L. Esmon, and C.T. Esmon. 2007. Regulated endothelial protein C receptor shedding is mediated by tumor necrosis factor-alpha converting enzyme/ADAM17. Journal of Thrombosis and Haemostasis 5: 395–402.PubMedCrossRefGoogle Scholar
  25. 25.
    Menschikowski, M., A. Hagelgans, G. Eisenhofer, and G. Siegert. 2009. Regulation of endothelial protein C receptor shedding by cytokines is mediated through differential activation of MAP kinase signaling pathways. Experimental Cell Research 315: 2673–2682.PubMedCrossRefGoogle Scholar
  26. 26.
    Michie, H.R., K.R. Manogue, D.R. Spriggs, et al. 1988. Detection of circulating tumor necrosis factor after endotoxin administration. New England Journal of Medicine 318: 1481–1486.PubMedCrossRefGoogle Scholar
  27. 27.
    Kremer, J.P., D. Jarrar, U. Steckholzer, and W. Ertel. 1996. Interleukin-1, −6 and tumor necrosis factor-alpha release is down-regulated in whole blood from septic patients. Acta Haematologica 95: 268–273.PubMedCrossRefGoogle Scholar
  28. 28.
    Yang, E.J., S.K. Ku, W. Lee, et al. 2013. Barrier protective effects of rosmarinic acid on HMGB1-induced inflammatory responses in vitro and in vivo. Journal of Cellular Physiology 228: 975–982.PubMedCrossRefGoogle Scholar
  29. 29.
    Buras, J.A., B. Holzmann, and M. Sitkovsky. 2005. Animal models of sepsis: setting the stage. Nature Reviews Drug Discovery 4: 854–865.PubMedCrossRefGoogle Scholar
  30. 30.
    Yang, H., M. Ochani, J. Li, et al. 2004. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proceedings of the National Academy of Sciences of the United States of America 101: 296–301.PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Han, H., B. Du, X. Pan, et al. 2010. CADPE inhibits PMA-stimulated gastric carcinoma cell invasion and matrix metalloproteinase-9 expression by FAK/MEK/ERK-mediated AP-1 activation. Molecular Cancer Research 8: 1477–1488.PubMedCrossRefGoogle Scholar
  32. 32.
    Leng, Y., T.L. Steiler, and J.R. Zierath. 2004. Effects of insulin, contraction, and phorbol esters on mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice. Diabetes 53: 1436–1444.PubMedCrossRefGoogle Scholar
  33. 33.
    Sesin, C.A., X. Yin, C.T. Esmon, J.P. Buyon, and R.M. Clancy. 2005. Shedding of endothelial protein C receptor contributes to vasculopathy and renal injury in lupus: in vivo and in vitro evidence. Kidney International 68: 110–120.PubMedCrossRefGoogle Scholar
  34. 34.
    Ware, L.B., E. Camerer, K. Welty-Wolf, M.J. Schultz, and M.A. Matthay. 2006. Bench to bedside: targeting coagulation and fibrinolysis in acute lung injury. American Journal of Physiology. Lung Cellular and Molecular Physiology 291: L307–L311.PubMedCrossRefGoogle Scholar
  35. 35.
    Esmon, C.T. 2005. The interactions between inflammation and coagulation. British Journal of Haematology 131: 417–430.PubMedCrossRefGoogle Scholar
  36. 36.
    Bae, J.S., L. Yang, and A.R. Rezaie. 2007. Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells. Proceedings of the National Academy of Sciences of the United States of America 104: 2867–2872.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    van Hylckama Vlieg, A., R. Montes, F.R. Rosendaal, and J. Hermida. 2007. Autoantibodies against endothelial protein C receptor and the risk of a first deep vein thrombosis. Journal of Thrombosis and Haemostasis 5: 1449–1454.PubMedCrossRefGoogle Scholar
  38. 38.
    Montes, R., V. Hurtado, A. Alonso, et al. 2005. Autoantibodies against the endothelial receptor of protein C are associated with acute myocardial infarction in young women. Journal of Thrombosis and Haemostasis 3: 1454–1458.PubMedCrossRefGoogle Scholar
  39. 39.
    Hurtado, V., R. Montes, J.C. Gris, et al. 2004. Autoantibodies against EPCR are found in antiphospholipid syndrome and are a risk factor for fetal death. Blood 104: 1369–1374.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Sae-Kwang Ku
    • 1
  • In-Chul Lee
    • 2
  • Min-Su Han
    • 3
  • Jong-Sup Bae
    • 4
  1. 1.Department of Anatomy and Histology, College of Korean MedicineDaegu Haany UniversityGyeongsanRepublic of Korea
  2. 2.Department of Cosmetic Science and TechnologySeowon UniversityCheongjuRepublic of Korea
  3. 3.Laboratory for Arthritis and Bone BiologyFatima Research Institute, Daegu Fatima HospitalDaeguRepublic of Korea
  4. 4.College of Pharmacy, CMRI, Research Institute of Pharmaceutical SciencesKyungpook National UniversityBuk-guRepublic of Korea

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