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Thrombin-Activated Protein C: Integrated to Regulate Vascular Physiology

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Thrombin

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Abstract

Thrombin has long been known to be a dual-faced molecule. On one hand, thrombin is the key procoagulant effector of the blood coagulation system; on the other, it is the only known physiological activator of the anticoagulant protein C pathway. This chapter will summarize recent results that thrombin and the protein C system are highly integrated to regulate not only thrombotic responses but also other aspects of vascular physiology that likely play key roles in the regulation of inflammatory responses.

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References

  • Abraham,. E., Reinhart, K., Opal, S., Demeyer, I., Doig, C., Rodriguez, A.L., Beale, R., Svoboda, P., Laterre, P.F., Simon, S., et al. 2003Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238–247.

    Article  PubMed  CAS  Google Scholar 

  • Abraham, E., Laterre, P.F., Garg, R., Levy, H., Talwar, D., Trzaskoma, B.L., Francois, B., Guy, J.S., Bruckmann, M., Rea-Neto, A., et al. 2005. Drotrecogin alfa (activated) for adults with severe sepsis and a low risk of death. N. Engl. J. Med. 353:1332–1341.

    Article  PubMed  CAS  Google Scholar 

  • Bae, J.S., Yang, L., Manithody, C., and Rezaie, A.R. 2007a. Engineering a disulfide bond to stabilize the calcium-binding loop of activated protein C eliminates its anticoagulant but not its protective signaling properties. J. Biol. Chem. 282:9251–9259.

    Article  CAS  Google Scholar 

  • Bae, J.S., Yang, L., Manithody, C., and Rezaie, A.R. 2007b. The ligand occupancy of endothelial protein C receptor switches the protease-activated receptor 1-dependent signaling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110:3909–3916.

    Article  CAS  Google Scholar 

  • Bae, J.S., Yang, L., and Rezaie, A.R. 2007c. Receptors of the protein C activation and activated protein C signaling pathways are colocalized in lipid rafts of endothelial cells. Proc. Natl. Acad. Sci. USA 104:2867–2872.

    Article  CAS  Google Scholar 

  • Bar-Shavit, R., Benezra, M., Sabbah, V., Bode, W., and Vlodavsky, I. 1992. Thrombin as a multifunctional protein: induction of cell adhesion and proliferation. Am. J. Respir. Cell Mol. Biol. 6:123–130.

    Article  PubMed  CAS  Google Scholar 

  • 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., et al. 2001. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 344:699–709.

    Article  PubMed  CAS  Google Scholar 

  • Camerer, E., Cornelissen, I., Kataoka, H., Duong, D.N., Zheng, Y.W., and Coughlin, S.R. 2006. Roles of protease-activated receptors in a mouse model of endotoxemia. Blood 107:3912–3921.

    Article  PubMed  CAS  Google Scholar 

  • Cheng, T., Liu, D., Griffin, J.H., Fernandez, J.A., Castellino, F., Rosen, E.D., Fukudome, K., and Zlokovic, B.V. 2003. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med. 9:338–342.

    Article  PubMed  CAS  Google Scholar 

  • Coughlin, S.R. 2000. Thrombin signalling and protease-activated receptors. Nature 407:258–264.

    Article  PubMed  CAS  Google Scholar 

  • Coughlin, S.R. 2005. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J. Thromb. Haemost. 3:1800–1814.

    Article  PubMed  CAS  Google Scholar 

  • Coughlin, S.R., and Camerer, E. 2003. PARticipation in inflammation. J. Clin. Invest. 111:25–27.

    PubMed  CAS  Google Scholar 

  • Creasey, A.A., Chang, A.C., Feigen, L., Wun, T.C., Taylor, F.B., Jr.,Hinshaw, L.B. 1993. Tissue factor pathway inhibitor reduces mortality from Escherichia coli. septic shock J. Clin. Invest. 91:2850–2856.

    Article  PubMed  CAS  Google Scholar 

  • Cunningham, M.A., Rondeau, E., Chen, X., Coughlin, S.R., Holdsworth, S.R., and Tipping, P.G. 2000. Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J. Exp. Med. 191:455–462.

    Article  PubMed  CAS  Google Scholar 

  • Dahlbäck, B. 1995. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 85:607–614.

    PubMed  Google Scholar 

  • Dahlback, B., and Villoutreix, B.O. 2005. Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure–function relationships and molecular recognition. Arterioscler. Thromb. Vasc. Biol. 25:1311–1320.

    Article  PubMed  Google Scholar 

  • Domotor, E., Benzakour, O., Griffin, J.H., Yule, D., Fukudome, K., and Zlokovic, B.V. 2003. Activated protein C alters cytosolic calcium flux in human brain endothelium via binding to endothelial protein C receptor and activation of protease activated receptor-1. Blood 101:4797–4801.

    Article  PubMed  Google Scholar 

  • Esmon, C.T. 1995. Thrombomodulin as a model of molecular mechanisms that modulate protease specificity and function at the vessel surface. FASEB J. 9:946–955.

    PubMed  CAS  Google Scholar 

  • Esmon, C.T. 2003. The protein C pathway. Chest 124:26S–32S.

    Article  PubMed  CAS  Google Scholar 

  • Esmon, C.T. 2005. The interactions between inflammation and coagulation. Br. J. Haematol. 131:417–430.

    Article  PubMed  CAS  Google Scholar 

  • Esmon, C.T., Xu, J., Gu, J.M., Qu, D., Laszik, Z., Ferrell, G., Stearns-Kurosawa, D.J., Kurosawa, S., Taylor, F.B., Jr.,Esmon, N.L. 1999. Endothelial protein C receptor. Thromb. Haemost. 82:251–258.

    PubMed  CAS  Google Scholar 

  • Faust, S.N., Levin, M., Harrison, O.B., Goldin, R.D., Lockhart, M.S., Kondaveeti, S., Laszik, Z., Esmon, C.T., and Heyderman, R.S. 2001. Dysfunction of endothelial protein C activation in severe meningococcal sepsis. N. Engl. J. Med. 345:408–416.

    Article  PubMed  CAS  Google Scholar 

  • Feistritzer, C., and Riewald, M. 2005. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105:3178–3184.

    Article  PubMed  CAS  Google Scholar 

  • Feistritzer, C., Schuepbach, R.A., Mosnier, L.O., Bush, L.A., Di Cera, E., Griffin, J.H., and Riewald, M. 2006. Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J. Biol. Chem. 281:20077–20084.

    Article  PubMed  CAS  Google Scholar 

  • Finigan, J.H., Dudek, S.M., Singleton, P.A., Chiang, E.T., Jacobson, J.R., Camp, S.M., Ye, S.Q., and Garcia, J.G. 2005. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J. Biol. Chem. 280:17286–17293.

    Article  PubMed  CAS  Google Scholar 

  • Flynn, A.N., and Buret, A.G. 2004. Proteinase-activated receptor 1 (PAR-1) and cell apoptosis. Apoptosis 9:729–737.

    Article  PubMed  CAS  Google Scholar 

  • Fukudome, K., and Esmon, C.T. 1994. Identification, cloning, and regulation of a novel endothelial cell protein C/activated protein C receptor. J. Biol. Chem. 269:26486–26491.

    PubMed  CAS  Google Scholar 

  • Ganopolsky, J.G., and Castellino, F.J. 2004. A protein C deficiency exacerbates inflammatory and hypotensive responses in mice during polymicrobial sepsis in a cecal ligation and puncture model. Am. J. Pathol. 165:1433–1446.

    Article  PubMed  CAS  Google Scholar 

  • Griffin, J.H., Evatt, B., Zimmerman, T.S., Kleiss, A.J., and Wideman, C. 1981. Deficiency of protein C in congenital thrombotic disease. J. Clin. Invest. 68:1370–1373.

    Article  PubMed  CAS  Google Scholar 

  • Gruber, A., Cantwell, A.M., Di Cera, E., and Hanson, S.R. 2002. The thrombin mutant W215A/E217A shows safe and potent anticoagulant and antithrombotic effects in vivo. J. Biol. Chem. 277:27581–27584.

    Article  PubMed  CAS  Google Scholar 

  • Guo, H., Liu, D., Gelbard, H., Cheng, T., Insalaco, R., Fernandez, J.A., Griffin, J.H., and Zlokovic, B.V. 2004. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 41:563–572.

    Article  PubMed  CAS  Google Scholar 

  • Hanson, S.R., Griffin, J.H., Harker, L.A., Kelly, A.B., Esmon, C.T., and Gruber, A. 1993. Antithrombotic effects of thrombin-induced activation of endogenous protein C in primates. J. Clin. Invest. 92:2003–2012.

    Article  PubMed  CAS  Google Scholar 

  • Heeb, M.J., Schwarz, H.P., White, T., Lammle, B., Berrettini, M., and Griffin, J.H. 1988. Immunoblotting studies of the molecular forms of protein C in plasma. Thromb. Res. 52:33–43.

    Article  PubMed  CAS  Google Scholar 

  • Hoffmann, J.N., Vollmar, B., Laschke, M.W., Inthorn, D., Fertmann, J., Schildberg, F.W., and Menger, M.D. 2004. Microhemodynamic and cellular mechanisms of activated protein C action during endotoxemia. Crit. Care Med. 32:1011–1017.

    Article  PubMed  Google Scholar 

  • Hopkins, P.C., Pike, R.N., and Stone, S.R. 2000. Evolution of serpin specificity: cooperative interactions in the reactive-site loop sequence of antithrombin specifically restrict the inhibition of activated protein C. J. Mol. Evol. 51:507–515.

    PubMed  CAS  Google Scholar 

  • Iba, T., Kidokoro, A., Fukunaga, M., Nagakari, K., Shirahama, A., and Ida, Y. 2005. Activated protein C improves the visceral microcirculation by attenuating the leukocyte–endothelial interaction in a rat lipopolysaccharide model. Crit. Care Med. 33:368–372.

    Article  PubMed  CAS  Google Scholar 

  • Isobe, H., Okajima, K., Uchiba, M., Mizutani, A., Harada, N., Nagasaki, A., and Okabe, K. 2001. Activated protein C prevents endotoxin-induced hypotension in rats by inhibiting excessive production of nitric oxide. Circulation 104:1171–1175.

    Article  PubMed  CAS  Google Scholar 

  • Joyce, D.E., Gelbert, L., Ciaccia, A., DeHoff, B., and Grinnell, B.W. 2001. Gene expression profile of antithrombotic protein C defines new mechanisms modulating inflammation and apoptosis. J. Biol. Chem. 276:11199–11203.

    Article  PubMed  CAS  Google Scholar 

  • Kaneider, N.C., Leger, A.J., Agarwal, A., Nguyen, N., Perides, G., Derian, C., Covic, L., and Kuliopulos, A. 2007. ‘Role reversal’ for the receptor PAR1 in sepsis-induced vascular damage. Nat. Immunol. 8:1303–1312.

    Article  PubMed  CAS  Google Scholar 

  • Kerschen, E.J., Fernandez, J.A., Cooley, B.C., Yang, X.V., Sood, R., Mosnier, L.O., Castellino, F.J., Mackman, N., Griffin, J.H., and Weiler, H. 2007. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J. Exp. Med. 204:2439–2448.

    Article  PubMed  CAS  Google Scholar 

  • Kuliopulos, A., Covic, L., Seeley, S.K., Sheridan, P.J., Helin, J., and Costello, C.E. 1999. Plasmin desensitization of the PAR1 thrombin receptor: kinetics, sites of truncation, and implications for thrombolytic therapy. Biochemistry 38:4572–4585.

    Article  PubMed  CAS  Google Scholar 

  • Laposata, M., Dovnarsky, D.K., and Shin, H.S. 1983. Thrombin-induced gap formation in confluent endothelial cell monolayers in vitro. Blood 62:549–556.

    PubMed  CAS  Google Scholar 

  • Laszik, Z., Mitro, A., Taylor, F.B., Jr., Ferrell, G., and Esmon, C.T. 1997. Human protein C receptor is present primarily on endothelium of large blood vessels: implications for the control of the protein C pathway. Circulation 96:3633–3640.

    Article  PubMed  CAS  Google Scholar 

  • Lay, A.J., Liang, Z., Rosen, E.D., and Castellino, F.J. 2005. Mice with a severe deficiency in protein C display prothrombotic and proinflammatory phenotypes and compromised maternal reproductive capabilities. J. Clin. Invest. 115:1552–1561.

    Article  PubMed  CAS  Google Scholar 

  • Lay, A.J., Donahue, D., Tsai, M.J., and Castellino, F.J. 2007. Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. Blood 109:1984–1991.

    Article  PubMed  CAS  Google Scholar 

  • Lee, M.J., Thangada, S., Claffey, K.P., Ancellin, N., Liu, C.H., Kluk, M., Volpi, M., Sha’afi, R.I., and Hla, T. 1999. Vascular endothelial cell adherens junction assembly and morphogenesis induced by sphingosine-1-phosphate. Cell 99:301–312.

    Article  PubMed  CAS  Google Scholar 

  • Levi, M., van der Poll, T., and Buller, H.R. 2004. Bidirectional relation between inflammation and coagulation. Circulation 109:2698–2704.

    Article  PubMed  Google Scholar 

  • Liaw, P.C., Mather, T., Oganesyan, N., Ferrell, G.L., and Esmon, C.T. 2001. Identification of the protein C/activated protein C binding sites on the endothelial cell protein C receptor. Implications for a novel mode of ligand recognition by a major histocompatibility complex class 1-type receptor. J. Biol. Chem. 276:8364–8370.

    Article  PubMed  CAS  Google Scholar 

  • Liaw, P.C., Esmon, C.T., Kahnamoui, K., Schmidt, S., Kahnamoui, S., Ferrell, G., Beaudin, S., Julian, J.A., Weitz, J.I., Crowther, M.,. et al. 2004. Patients with severe sepsis vary markedly in their ability to generate activated protein C. Blood 104:3958–3964.

    Article  PubMed  CAS  Google Scholar 

  • Ludeman, M.J., Kataoka, H., Srinivasan, Y., Esmon, N.L., Esmon, C.T., and Coughlin, S.R. 2005. PAR1 cleavage and signaling in response to activated protein C and thrombin. J. Biol. Chem. 280:13122–13128.

    Article  PubMed  CAS  Google Scholar 

  • McLaughlin, J.N., Mazzoni, M.R., Cleator, J.H., Earls, L., Perdigoto, A.L., Brooks, J.D., Muldowney, J.A., IIIVaughan, D.E., and Hamm, H.E. 2005a. Thrombin modulates the expression of a set of genes including thrombospondin-1 in human microvascular endothelial cells. J. Biol. Chem. 280:22172–22180.

    Article  CAS  Google Scholar 

  • McLaughlin, J.N., Shen, L., Holinstat, M., Brooks, J.D., Dibenedetto, E., and Hamm, H.E. 2005b. Functional selectivity of G protein signaling by agonist peptides and thrombin for the protease-activated receptor-1. J. Biol. Chem. 280:25048–25059.

    Article  CAS  Google Scholar 

  • McVerry, B.J., and Garcia, J.G. 2005. In vitro and in vivo modulation of vascular barrier integrity by sphingosine 1-phosphate: mechanistic insights. Cell Signal. 17:131–139.

    Article  PubMed  CAS  Google Scholar 

  • Mizutani, A., Okajima, K., Uchiba, M., and Noguchi, T. 2000. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 95:3781–3787.

    PubMed  CAS  Google Scholar 

  • Mosnier, L.O., and Griffin, J.H. 2003. Inhibition of staurosporine-induced apoptosis of endothelial cells by activated protein C requires protease-activated receptor-1 and endothelial cell protein C receptor. Biochem. J. 373:65–70.

    Article  PubMed  CAS  Google Scholar 

  • Mosnier, L.O., and Griffin, J.H. 2006. Protein C anticoagulant activity in relation to anti-inflammatory and anti-apoptotic activities. Front. Biosci. 11:2381–2399.

    Article  PubMed  CAS  Google Scholar 

  • Mosnier, L.O., Gale, A.J., Yegneswaran, S., and Griffin, J.H. 2004. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 104:1740–1744.

    Article  PubMed  CAS  Google Scholar 

  • Mosnier, L.O., Zlokovic, B.V., and Griffin, J.H. 2007. The cytoprotective protein C pathway. Blood 109:3161–3172.

    Article  PubMed  CAS  Google Scholar 

  • Murakami, K., Okajima, K., Uchiba, M., Johno, M., Nakagaki, T., Okabe, H., and Takatsuki, K. 1996. Activated protein C attenuates endotoxin-induced pulmonary vascular injury by inhibiting activated leukocytes in rats. Blood 87:642–647.

    PubMed  CAS  Google Scholar 

  • Murakami, K., Okajima, K., Uchiba, M., Johno, M., Nakagaki, T., Okabe, H., and Takatsuki, K. 1997. Activated protein C prevents LPS-induced pulmonary vascular injury by inhibiting cytokine production. Am. J. Physiol. 272:L197–L202.

    PubMed  CAS  Google Scholar 

  • Nakanishi-Matsui, M., Zheng, Y.W., Sulciner, D.J., Weiss, E.J., Ludeman, M.J., and Coughlin, S.R. 2000. PAR3 is a cofactor for PAR4 activation by thrombin. Nature 404:609–613.

    Article  PubMed  CAS  Google Scholar 

  • O’Brien, L.A., Richardson, M.A., Mehrbod, S.F., Berg, D.T., Gerlitz, B., Gupta, A., and Grinnell, B.W. 2007. Activated protein C decreases tumor necrosis factor related apoptosis-inducing ligand by an EPCR-independent mechanism involving Egr-1/Erk-1/2 activation. Arterioscler. Thromb. Vasc. Biol. 27:2634–2641.

    Article  PubMed  Google Scholar 

  • O’Brien, P.J., Molino, M., Kahn, M., and Brass, L.F. 2001. Protease activated receptors: theme and variations. Oncogene 20:1570–1581.

    Article  PubMed  Google Scholar 

  • Opal, S.M. 2000. Phylogenetic and functional relationships between coagulation and the innate immune response. Crit. Care Med. 28:S77–S80.

    Article  PubMed  CAS  Google Scholar 

  • Ossovskaya, V.S., and Bunnett, N.W. 2004. Protease-activated receptors: contribution to physiology and disease. Physiol. Rev. 84:579–621.

    Article  PubMed  CAS  Google Scholar 

  • Parry, M.A., Myles, T., Tschopp, J., and Stone, S.R. 1996. Cleavage of the thrombin receptor: identification of potential activators and inactivators. Biochem. J. 320:335–341.

    PubMed  CAS  Google Scholar 

  • Pawlinski, R., Pedersen, B., Schabbauer, G., Tencati, M., Holscher, T., Boisvert, W., Andrade-Gordon, P., Frank, R.D., and Mackman, N. 2004. Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 103:1342–1347.

    Article  PubMed  CAS  Google Scholar 

  • Regan, L.M., Mollica, J.S., Rezaie, A.R., and Esmon, C.T. 1997. The interaction between the endothelial cell protein C receptor and protein C is dictated by the gamma-carboxyglutamic acid domain of protein C. J. Biol. Chem. 272:26279–26284.

    Article  PubMed  CAS  Google Scholar 

  • Riewald, M., and Ruf, W. 2005. Protease-activated receptor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling. J. Biol. Chem. 280:19808–19814.

    Article  PubMed  CAS  Google Scholar 

  • Riewald, M., Petrovan, R.J., Donner, A., Mueller, B.M., and Ruf, W. 2002. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 296:1880–1882.

    Article  PubMed  CAS  Google Scholar 

  • Sambrano, G.R., Weiss, E.J., Zheng, Y.W., Huang, W., and Coughlin, S.R. 2001. Role of thrombin signalling in platelets in haemostasis and thrombosis. Nature 413:74–78.

    Article  PubMed  CAS  Google Scholar 

  • Schuepbach, R.A., Feistritzer, C., Brass, L.F., and Riewald, M. 2008. Activated protein C-cleaved protease activated receptor-1 is retained on the endothelial cell surface even in the presence of thrombin. Blood 111:2667–2673.

    Article  PubMed  CAS  Google Scholar 

  • Sevastos, J., Kennedy, S.E., Davis, D.R., Sam, M., Peake, P.W., Charlesworth, J.A., Mackman, N., and Erlich, J.H. 2007. Tissue factor deficiency and PAR-1 deficiency are protective against renal ischemia reperfusion injury. Blood 109:577–583.

    Article  PubMed  CAS  Google Scholar 

  • Shapiro, M.J., and Coughlin, S.R. 1998. Separate signals for agonist-independent and agonist-triggered trafficking of protease-activated receptor 1. J. Biol. Chem. 273:29009–29014.

    Article  PubMed  CAS  Google Scholar 

  • Striggow, F., Riek, M., Breder, J., Henrich-Noack, P., Reymann, K.G., and Reiser, G. 2000. The protease thrombin is an endogenous mediator of hippocampal neuroprotection against ischemia at low concentrations but causes degeneration at high concentrations. Proc. Natl. Acad. Sci. USA 97:2264–2269.

    Article  PubMed  CAS  Google Scholar 

  • Sugama, Y., and Malik, A.B. 1992. Thrombin receptor 14-amino acid peptide mediates endothelial hyperadhesivity and neutrophil adhesion by P-selectin-dependent mechanism. Circ. Res. 71:1015–1019.

    Article  PubMed  CAS  Google Scholar 

  • Sugama, Y., Tiruppathi, C., offakidevi, K., Andersen, T.T., Fenton, J.W., and IIMalik, A.B. 1992. Thrombin-induced expression of endothelial P-selectin and intercellular adhesion molecule-1: a mechanism for stabilizing neutrophil adhesion. J. Cell Biol. 119:935–944.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, F.B., Chang, A., Esmon, C.T., D’Angelo, A., Vigano-D’Angelo, S., and Blick, K.E. 1987. Protein C prevents the coagulopathic and lethal effects of Escherichia coli. infusion in the baboon J. Clin. Invest. 79:918–925.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, F.B., Chang, A.C., Peer, G., Li, A., Ezban, M., and Hedner, U. 1998. Active site inhibited factor VIIa (DEGR VIIa) attenuates the coagulant and interleukin-6 and -8, but not tumor necrosis factor, responses of the baboon to LD100 Escherichia coli. Blood 91:1609–1615.

    PubMed  CAS  Google Scholar 

  • Taylor, F.B., Stearns-Kurosawa, D.J., Kurosawa, S., Ferrell, G., Chang, A.C., Laszik, Z., Kosanke, S., Peer, G., and Esmon, C.T. 2000. The endothelial cell protein C receptor aids in host defense against Escherichia coli. sepsis Blood 95:1680–1686.

    PubMed  CAS  Google Scholar 

  • Taylor, F.B., Jr., Chang, A., Hinshaw, L.B., Esmon, C.T., Archer, L.T., and Beller, B.K. 1984. A model for thrombin protection against endotoxin. Thromb. Res. 36:177–185.

    Article  PubMed  CAS  Google Scholar 

  • Taylor, F.B., Jr., Chang, A., Ruf, W., Morrissey, J.H., Hinshaw, L., Catlett, R., Blick, K., and Edgington, T.S. 1991a. Lethal E. coli. septic shock is prevented by blocking tissue factor with monoclonal antibody Circ. Shock 33:127–134.

    Google Scholar 

  • Taylor, F.B., Jr., Chang, A.C., Peer, G.T., Mather, T., Blick, K., Catlett, R., Lockhart, M.S., and Esmon, C.T. 1991b. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli. without preventing shock or organ damage Blood 78:364–368.

    Google Scholar 

  • Trejo, J. 2003. Protease-activated receptors: new concepts in regulation of G protein-coupled receptor signaling and trafficking. J. Pharmacol. Exp. Ther. 307:437–442.

    Article  PubMed  CAS  Google Scholar 

  • Uchiba, M., Okajima, K., Oike, Y., Ito, Y., Fukudome, K., Isobe, H., and Suda, T. 2004. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ. Res. 95:34–41.

    Article  PubMed  CAS  Google Scholar 

  • Vergnolle, N., Cellars, L., Mencarelli, A., Rizzo, G., Swaminathan, S., Beck, P., Steinhoff, M., Andrade-Gordon, P., Bunnett, N.W., Hollenberg, M.D.,. et al. 2004. A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J. Clin. Invest. 114:1444–1456.

    PubMed  CAS  Google Scholar 

  • Vouret-Craviari, V., Boquet, P., Pouyssegur, J., and Van Obberghen-Schilling, E. 1998. Regulation of the actin cytoskeleton by thrombin in human endothelial cells: role of Rho proteins in endothelial barrier function. Mol. Biol. Cell 9:2639–2653.

    Article  PubMed  CAS  Google Scholar 

  • Vu, T.K., Hung, D.T., Wheaton, V.I., and Coughlin, S.R. 1991a. Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation. Cell 64:1057–1068.

    Article  CAS  Google Scholar 

  • Vu, T.K., Wheaton, V.I., Hung, D.T., Charo, I., and Coughlin, S.R. 1991b. Domains specifying thrombin–receptor interaction. Nature 353:674–677.

    Article  CAS  Google Scholar 

  • Warren, B.L., Eid, A., Singer, P., Pillay, S.S., Carl, P., Novak, I., Chalupa, P., Atherstone, A., Penzes, I., Kubler, A.,. et al. 2001. Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878.

    Article  PubMed  CAS  Google Scholar 

  • Weiss, E.J., Hamilton, J.R., Lease, K.E., and Coughlin, S.R. 2002. Protection against thrombosis in mice lacking PAR3. Blood 100:3240–3244.

    Article  PubMed  CAS  Google Scholar 

  • Whetzel, A.M., Bolick, D.T., Srinivasan, S., Macdonald, T.L., Morris, M.A., Ley, K., and Hedrick, C.C. 2006. Sphingosine-1 phosphate prevents monocyte/endothelial interactions in type 1 diabetic NOD mice through activation of the S1P1 receptor. Circ. Res. 99:731–739.

    Article  PubMed  CAS  Google Scholar 

  • Zeng, W., Matter, W.F., Yan, S.B., Um, S.L., Vlahos, C.J., and Liu, L. 2004. Effect of drotrecogin alfa (activated) on human endothelial cell permeability and Rho kinase signaling. Crit. Care Med. 32:S302–S308.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Immunology SP30-3040, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA

    Matthias Riewald

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  1. Matthias Riewald
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Correspondence to Matthias Riewald .

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  1. Medical School, University of Patras, Patras, Greece

    Michael E. Maragoudakis  & Nikos E. Tsopanoglou  & 

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© 2009 Springer Science+Business Media, LLC

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Riewald, M. (2009). Thrombin-Activated Protein C: Integrated to Regulate Vascular Physiology. In: Maragoudakis, M., Tsopanoglou, N. (eds) Thrombin. Springer, New York, NY. https://doi.org/10.1007/978-0-387-09637-7_4

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