Skip to main content
Biochemical Journal logoLink to Biochemical Journal
. 2003 Jul 1;373(Pt 1):65–70. doi: 10.1042/BJ20030341

Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor.

Laurent O Mosnier 1, John H Griffin 1
PMCID: PMC1223481  PMID: 12683950

Abstract

In a model of staurosporine-induced apoptosis using EAhy926 endothelial cells, inhibition of apoptosis by activated protein C was dose-dependent and required the enzyme's active site, implicating activated protein C-mediated proteolysis. Consistent with this implication, both protease-activated receptor-1 (PAR-1) and endothelial cell protein C receptor (EPCR) were required for the anti-apoptotic effects of activated protein C.

Full Text

The Full Text of this article is available as a PDF (197.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abraham E., Reinhart K., Svoboda P., Seibert A., Olthoff D., Dal Nogare A., Postier R., Hempelmann G., Butler T., Martin E. Assessment of the safety of recombinant tissue factor pathway inhibitor in patients with severe sepsis: a multicenter, randomized, placebo-controlled, single-blind, dose escalation study. Crit Care Med. 2001 Nov;29(11):2081–2089. doi: 10.1097/00003246-200111000-00007. [DOI] [PubMed] [Google Scholar]
  2. Bernard G. R., Vincent J. L., Laterre P. F., LaRosa S. P., Dhainaut J. F., Lopez-Rodriguez A., Steingrub J. S., Garber G. E., Helterbrand J. D., Ely E. W. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med. 2001 Mar 8;344(10):699–709. doi: 10.1056/NEJM200103083441001. [DOI] [PubMed] [Google Scholar]
  3. Cheng Tong, Liu Dong, Griffin John H., Fernández José A., Castellino Francis, Rosen Elliot D., Fukudome Kenji, Zlokovic Berislav V. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med. 2003 Feb 3;9(3):338–342. doi: 10.1038/nm826. [DOI] [PubMed] [Google Scholar]
  4. Conway Edward M., Van de Wouwer Marlies, Pollefeyt Saskia, Jurk Kerstin, Van Aken Hugo, De Vriese Astrid, Weitz Jeffrey I., Weiler Hartmut, Hellings Peter W., Schaeffer Paul. The lectin-like domain of thrombomodulin confers protection from neutrophil-mediated tissue damage by suppressing adhesion molecule expression via nuclear factor kappaB and mitogen-activated protein kinase pathways. J Exp Med. 2002 Sep 2;196(5):565–577. doi: 10.1084/jem.20020077. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Coughlin S. R. Thrombin signalling and protease-activated receptors. Nature. 2000 Sep 14;407(6801):258–264. doi: 10.1038/35025229. [DOI] [PubMed] [Google Scholar]
  6. Edgell C. J., McDonald C. C., Graham J. B. Permanent cell line expressing human factor VIII-related antigen established by hybridization. Proc Natl Acad Sci U S A. 1983 Jun;80(12):3734–3737. doi: 10.1073/pnas.80.12.3734. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Esmon C. T. Regulation of blood coagulation. Biochim Biophys Acta. 2000 Mar 7;1477(1-2):349–360. doi: 10.1016/s0167-4838(99)00266-6. [DOI] [PubMed] [Google Scholar]
  8. Esmon C. T. The endothelial cell protein C receptor. Thromb Haemost. 2000 May;83(5):639–643. [PubMed] [Google Scholar]
  9. Esmon Charles T. Protein C pathway in sepsis. Ann Med. 2002;34(7-8):598–605. doi: 10.1080/078538902321117823. [DOI] [PubMed] [Google Scholar]
  10. Fuentes-Prior P., Iwanaga Y., Huber R., Pagila R., Rumennik G., Seto M., Morser J., Light D. R., Bode W. Structural basis for the anticoagulant activity of the thrombin-thrombomodulin complex. Nature. 2000 Mar 30;404(6777):518–525. doi: 10.1038/35006683. [DOI] [PubMed] [Google Scholar]
  11. Fukudome K., Esmon C. T. Molecular cloning and expression of murine and bovine endothelial cell protein C/activated protein C receptor (EPCR). The structural and functional conservation in human, bovine, and murine EPCR. J Biol Chem. 1995 Mar 10;270(10):5571–5577. doi: 10.1074/jbc.270.10.5571. [DOI] [PubMed] [Google Scholar]
  12. Gale A. J., Sun X., Heeb M. J., Griffin J. H. Nonenzymatic anticoagulant activity of the mutant serine protease Ser360Ala-activated protein C mediated by factor Va. Protein Sci. 1997 Jan;6(1):132–140. doi: 10.1002/pro.5560060115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Griffin John H., Zlokovic Berislav, Fernández José A. Activated protein C: potential therapy for severe sepsis, thrombosis, and stroke. Semin Hematol. 2002 Jul;39(3):197–205. doi: 10.1053/shem.2002.34093. [DOI] [PubMed] [Google Scholar]
  14. Heeb M. J., Schwarz H. P., White T., Lämmle B., Berrettini M., Griffin J. H. Immunoblotting studies of the molecular forms of protein C in plasma. Thromb Res. 1988 Oct 1;52(1):33–43. doi: 10.1016/0049-3848(88)90038-2. [DOI] [PubMed] [Google Scholar]
  15. Idziorek T., Estaquier J., De Bels F., Ameisen J. C. YOPRO-1 permits cytofluorometric analysis of programmed cell death (apoptosis) without interfering with cell viability. J Immunol Methods. 1995 Sep 25;185(2):249–258. doi: 10.1016/0022-1759(95)00172-7. [DOI] [PubMed] [Google Scholar]
  16. Isobe H., Okajima K., Uchiba M., Mizutani A., Harada N., Nagasaki A., Okabe K. Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation. 2001 Sep 4;104(10):1171–1175. doi: 10.1161/hc3501.093799. [DOI] [PubMed] [Google Scholar]
  17. Joyce D. E., Gelbert L., Ciaccia A., DeHoff B., Grinnell B. W. Gene expression profile of antithrombotic protein c defines new mechanisms modulating inflammation and apoptosis. J Biol Chem. 2001 Feb 5;276(14):11199–11203. doi: 10.1074/jbc.C100017200. [DOI] [PubMed] [Google Scholar]
  18. Kuliopulos A., Covic L., Seeley S. K., Sheridan P. J., Helin J., Costello C. E. Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry. 1999 Apr 6;38(14):4572–4585. doi: 10.1021/bi9824792. [DOI] [PubMed] [Google Scholar]
  19. Oganesyan Vaheh, Oganesyan Natalia, Terzyan Simon, Qu Dongfeng, Dauter Zbigniew, Esmon Naomi L., Esmon Charles T. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem. 2002 May 28;277(28):24851–24854. doi: 10.1074/jbc.C200163200. [DOI] [PubMed] [Google Scholar]
  20. Regan L. M., Stearns-Kurosawa D. J., Kurosawa S., Mollica J., Fukudome K., Esmon C. T. The endothelial cell protein C receptor. Inhibition of activated protein C anticoagulant function without modulation of reaction with proteinase inhibitors. J Biol Chem. 1996 Jul 19;271(29):17499–17503. doi: 10.1074/jbc.271.29.17499. [DOI] [PubMed] [Google Scholar]
  21. Riewald Matthias, Petrovan Ramona J., Donner Aaron, Mueller Barbara M., Ruf Wolfram. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science. 2002 Jun 7;296(5574):1880–1882. doi: 10.1126/science.1071699. [DOI] [PubMed] [Google Scholar]
  22. Rothbarth K., Dabaghian A. R., Stammer H., Werner D. One single mRNA encodes the centrosomal protein CCD41 and the endothelial cell protein C receptor (EPCR). FEBS Lett. 1999 Sep 10;458(1):77–80. doi: 10.1016/s0014-5793(99)01074-1. [DOI] [PubMed] [Google Scholar]
  23. Shua F., Kobayashia H., Fukudomeb K., Tsuneyoshib N., Kimotob M., Teraoa T. Activated protein C suppresses tissue factor expression on U937 cells in the endothelial protein C receptor-dependent manner. FEBS Lett. 2000 Jul 21;477(3):208–212. doi: 10.1016/s0014-5793(00)01740-3. [DOI] [PubMed] [Google Scholar]
  24. Stearns-Kurosawa D. J., Kurosawa S., Mollica J. S., Ferrell G. L., Esmon C. T. The endothelial cell protein C receptor augments protein C activation by the thrombin-thrombomodulin complex. Proc Natl Acad Sci U S A. 1996 Sep 17;93(19):10212–10216. doi: 10.1073/pnas.93.19.10212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Taylor F. B., Jr, Stearns-Kurosawa D. J., Kurosawa S., Ferrell G., Chang A. C., Laszik Z., Kosanke S., Peer G., Esmon C. T. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood. 2000 Mar 1;95(5):1680–1686. [PubMed] [Google Scholar]
  26. Warren B. L., Eid A., Singer P., Pillay S. S., Carl P., Novak I., Chalupa P., Atherstone A., Pénzes I., Kübler A. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA. 2001 Oct 17;286(15):1869–1878. doi: 10.1001/jama.286.15.1869. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES