The protein C pathway and pathologic processes

Journal of Thrombosis and Haemostasis

Volumn 7, Issue SUPPL. 1, 2009, Pages 140-145

  Castellino, Francis J ^a   Ploplis, V A ^a  

^a UNIVERSITY OF NOTRE DAME   (United States)

Author keywords

Anticoagulation; Cell signaling; Cytoprotection; Inflammation; Protein C

Indexed keywords

ACTIVATED PROTEIN C; DROTRECOGIN; ENDOTHELIAL PROTEIN C RECEPTOR; INTERLEUKIN 1; INTERLEUKIN 6; MACROPHAGE INFLAMMATORY PROTEIN 2; PROSTAGLANDIN; PROTEIN C; PROTEIN S; PROTEINASE ACTIVATED RECEPTOR 1; THROMBIN ACTIVATABLE FIBRINOLYSIS INHIBITOR; THROMBOMODULIN; TUMOR NECROSIS FACTOR ALPHA;

ANTICOAGULATION; CELL PROTECTION; CEREBROVASCULAR ACCIDENT; CROHN DISEASE; CYTOKINE RELEASE; DISSEMINATED INTRAVASCULAR CLOTTING; DOWN REGULATION; DRUG EFFICACY; FIBRINOLYSIS; GENE ACTIVATION; GENE EXPRESSION; GENE FUNCTION; HUMAN; NONHUMAN; PHENOTYPE; PRIORITY JOURNAL; REVIEW; SEPSIS; SIGNAL TRANSDUCTION; SYSTEMIC INFLAMMATORY RESPONSE SYNDROME; ULCERATIVE COLITIS;

ANIMALS; CARDIOVASCULAR DISEASES; HUMANS; INFLAMMATION; PROTEIN C;

EID: 67849101852     PISSN: 15387933     EISSN: 15387836     Source Type: Journal    
DOI: 10.1111/j.1538-7836.2009.03410.x     Document Type: Review

References (82)

1. Kisiel W, Canfield WM, Ericsson LH, Davie EW. Anticoagulant properties of bovine plasma protein C following activation by thrombin. Biochemistry 1977; 16: 5824-31.
2. Vehar GA, Davie EW. Preparation and properties of bovine factor VIII (antihemophilic factor). Biochemistry 1980; 19: 401-10.
3. Joyce DE, Gelbert L, Ciaccia A, DeHoff B, Grinnell BW. Gene expression profile of antithrombin protein C defines new mechanisms modulating inflammation and apoptosis. J Biol Chem 2001; 276: 11199-203.
4. Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 2003; 9: 338-42.
5. Dömötör E, Benzakour O, Griffin JH, Yule D, Fukudome K, Zlokovic BV. 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 2003; 101: 4797-801.
6. Mosnier LO, Griffin JH. 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 2003; 373: 65-70.
7. Riewald M, Petrovan RJ, Donner A, Mueller BM, Ruf W. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002; 296: 1880-2.
8. Riewald M, Ruf W. Protease-activated receptor-1 signaling by activated protein C in cytokine perturbed endothelial cells is distinct from thrombin signaling. J Biol Chem 2005; 280: 19808-14.
9. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 2005; 105: 3178-84.
10. Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J, Derian CK, Andrade-Gordon P, Rosen H, Ruf W. Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 2008; 452: 654-8.
11. Yamamoto K, Loskutoff DJ. Extrahepatic expression and regulation of protein C in the mouse. Am J Pathol 1998; 153: 547-55.
12. Foster DC, Davie EW. Characterization of a cDNA coding for human protein C. Proc Natl Acad Sci USA 1984; 81: 4766-70.
13. Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257: 7944-7.
14. Stenflo J, Fernlund P. Amino acid sequence of the heavy chain of bovine protein C. J Biol Chem 1982; 257: 12180-90.
15. Bajzar L, Nesheim ME, Tracy PB. The profibrinolytic effect of activated protein C in clots formed from plasma is TAFI-dependent. Blood 1996; 88: 2093-100.
16. Taylor FB, Lockhart MS. A new function for activated protein C: activated protein C prevents inhibition of plasminogen activators by releasate from mononuclear leukocytes-platelet suspensions stimulated by phorbol diester. Thromb Res 1985; 37: 639-49.
17. Feistritzer C, Schuepbach RA, Mosnier LO, Bush LA, Di Cera E, Griffin JH, Riewald M. Protective signaling by activated protein C is mechanistically linked to protein C activation on endothelial cells. J Biol Chem 2006; 281: 20077-84.
18. Bae JS, Yang L, Manithody C, Rezaie AR. 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 2007; 110: 3909-16.
19. Bae JS, Yang L, Rezaie AR. 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 2007; 104: 2867-72.
20. Niessen F, Furlan-Fregula C, Fernandez JA, Mosnier LO, Castellino FJ, Weiller H, Rosen H, Griffin JH, Ruf W. Endogenous EPCR/aPC-PAR1 signaling prevents inflammatio-induced vascular leakage and lethality. Blood 2009: Doi: 10.1182/blood-2008-12-192385.
21. Steinemann S, Ulevitch RJ, Mackman N. Role of the lipopolysaccharide (LPS)-binding protein/CD14 pathway in LPS induction of tissue factor expression in monocytic cells. Arterioscler Thromb 1994; 14: 1202-9.
22. Oeth P, Parry GC, Mackman N. Regulation of the tissue factor gene in human monocytic cells. Role of AP-1, NF-kappa B/Rel, and Sp1 proteins in uninduced and lipopolysaccharide-induced expression. Arterioscler Thromb Vasc Biol 1997; 17: 365-74.
23. Guha M, Mackman N. The PI3K-Akt pathway limits LPS activation of signaling pathways and expression of inflammatory mediators in human monocytic cells. J Biol Chem 2002; 277: 32124-33.
24. Hirata M, Shimomura Y, Yoshida M, Wright SC, Larrick JW. Endotoxin-binding synthetic peptides with endotoxin-neutralizing, antibacterial and anticoagulant activities. Prog Clin Biol Res 1994; 388: 147-59.
25. Higure A, Okamoto K, Hirata K, Todoroki H, Nagafuchi Y, Takeda S, Katoh H, Itoh H, Ohsato K, Nakamura S. Macrophages and neutrophils infiltrating into the liver are responsible for tissue factor expression in a rabbit model of acute obstructive cholangitis. Thromb Haemost 1996; 75: 791-5.
26. Rashid J, Weiss DJ, Maheswaran SK, Murtaugh MP. In vitro expression and inhibition of procoagulant activity produced by bovine alveolar macrophages and peripheral blood cells. Vet Res Commun 1996; 20: 19-31.
27. Drake TA, Cheng J, Chang A, Taylor FB. Expression of tissue factor, thrombomodulin, and E-selectin in baboons with lethal Escherichia coli sepsis. Am J Pathol 1993; 142: 1458-70.
28. Parry GCN, Mackman N. Transcriptional regulation of tissue factor expression in human endothelial cells. Arterioscler Thromb Vasc Biol 1995; 15: 612-21.
29. Heyderman RS, Klein NJ, Daramola OA, Hammerschmidt S, Frosch M, Robertson BD, Levin M, Ison CA. Induction of human endothelial tissue factor expression by Neisseria meningitidis: The influence of bacterial killing and adherence to the endothelium. Microb Pathog 1997; 22: 265-74.
30. Todoroki H, Nakamura S, Higure A, Okamoto K, Takeda S, Nagata N, Itoh H, Ohsato K. Neutrophils express tissue factor in a monkey model of sepsis. Surgery 2000; 127: 209-16.
31. Gando S, Kameue T, Nanzaki S, Nakanishi Y. Cytokines, soluble thrombomodulin and disseminated intravascular coagulation in patients with systemic inflammatory response syndrome. Thromb Res 1995; 80: 519-26.
32. Bevilacqua MP, Pober JS, Majeau GR, Fiers W, Cotran RS, Gimbrone MA. Recombinant tumor necrosis factor induces procoagulant activity in cultured human vascular endothelium: Characterization and comparison with the actions of interleukin 1. Proc Natl Acad Sci USA 1986; 83: 4533-7.
33. Wada H, Tamaki S, Tanigawa M, Takagi M, Mori Y, Deguchi A, Katayama N, Yamamoto T, Deguchi KS. Plasma level of IL-1 beta in disseminated intravascular coagulation. Thromb Haemost 1991; 65: 364-8.
34. Fan J, Kapus A, Li YH, Rizoli S, Marshall JC, Rotstein OD. Priming for enhanced alveolar fibrin deposition after hemorrhagic shock: Role of tumor necrosis factor. Am J Respir Cell Mol Biol 2000; 22: 412-21.
35. Cunningham PN, Dyanov HM, Park P, Wang J, Newell KA, Quigg RJ. Acute renal failure in endotoxemia is caused by TNF acting directly on TNF receptor-1 in kidney. J Immunol 2002; 168: 5817-23.
36. Bevilacqua MP, Pober JS, Majeau GR, Cotran RS, Gimbrone MA. Interleukin 1 (IL-1) induces biosynthesis and cell surface expression of procoagulant activity in human vascular endothelial cells. J Exp Med 1984; 160: 618-23.
37. Nawroth PP, Handley DA, Esmon CT, Stern DM. Interleukin 1 induces endothelial cell procoagulant while suppressing cell-surface anticoagulant activity. Proc Natl Acad Sci USA 1986; 83: 3460-4.
38. Neumann FJ, Ott I, Marx N, Luther T, Kenngott S, Gawaz M, Kotzsch M, Schomig A. Effect of human recombinant interleukin-6 and interleukin-8 on monocyte procoagulant activity. Arterioscler Thromb Vasc Biol 1997; 17: 3399-405.
39. Nakae H, Endo S, Inada K, Takakuwa T, Kasai T, Yoshida M. Relationship between thromboxane B2 and 6-keto-prostaglandin F1 alpha in sepsis. Res Commun Chem Pathol Pharmacol 1994; 83: 297-302.
40. Maloney CG, Thompson SD, Hill HR, Bohnsack JF, McIntyre TM, Zimmerman GA. Induction of cyclooxygenase-2 by human monocytes exposed to group B streptococci. J Leuk Biol 2000; 67: 615-21.
41. Fourrier F, Chopin C, Goudemand J, Hendrycx S, Caron C, Rime A, Marey A, Lestavel P. Septic shock, multiple organ failure, and disseminated intravascular coagulation. Compared patterns of antithrombin III, protein C, and protein S deficiencies. Chest 1992; 101: 16-23.
42. Robbie LA, Dummer S, Booth NA, Adey GD, Bennett B. Plasminogen activator inhibitor 2 and urokinase-type plasminogen activator in plasma and leucocytes in patients with severe sepsis. Br J Haematol 2000; 109: 342-8.
43. de Boer JP, Creasy AA, Chang A, Roem D, Brouwer MC, Eerenberg AJ, Hack CE, Taylor F. Activation patterns of coagulation and fibrinolysis in baboons following infusion with lethal or sublethal dose of Escherichia coli. Circ Shock 1993; 39: 59-67.
44. Sato T, Miwa T, Akatsu H, Matsukawa N, Obata K, Okada N, Campbell W, Okada H. Pro-carboxypeptidase R is an acute phase protein in the mouse, whereas carboxypeptidase N is not. J Immunol 2000; 165: 1053-8.
45. Watanabe R, Wada H, Watanabe Y, Sakakura M, Nakasaki T, Mori Y, Nishikawa M, Gabazza EC, Nobori T, Shiku H. Activity and antigen levels of thrombin-activatable fibrinolysis inhibitor in plasma of patients with disseminated intravascular coagulation. Thromb Res 2001; 104: 1-6.
46. Hermans PW, Hibberd ML, Booy R, Daramola O, Hazelzet JA, de Groot R, Levin M. 4G/5G promoter polymorphism in the plasminogen-activator-inhibitor-1 gene and outcome of meningococcal disease. Meningococcal Research Group. Lancet 1999; 354: 556-60.
47. Park KJ, Kim HJ, Hwang SC, Lee SM, Lee YH, Hahn MH, Kim SK, Lee WY. The imbalance between coagulation and fibrinolysis is related to the severity of the illness and the prognosis in sepsis. Korean J Intern Med 1999; 14: 72-7.
48. Taylor FB, Chang AC, Peer GT, Mather T, Blick K, Catlett R, Lockhart MS, Esmon CT. DEGR-factor Xa blocks disseminated intravascular coagulation initiated by Escherichia coli without preventing shock or organ damage. Blood 1991; 78: 364-8.
49. Minnema MC, Chang AC, Jansen PM, Lubbers YT, Pratt BM, Whittaker BG, Taylor FB, Hack CE, Friedman B. Recombinant human antithrombin III improves survival and attenuates inflammatory responses in baboons lethally challenged with Escherichia coli. Blood 2000; 95: 1117-23.
50. Welty-Wolf KE, Carraway MS, Miller DL, Ortel TL, Ezban M, Ghio AJ, Idell S, Piantadosi CA. Coagulation blockade prevents sepsis-induced respiratory and renal failure in baboons. Am J Respir Crit Care Med 2001; 164: 1988-96.
51. Taylor FB, Chang A, Esmon CT, D'Angelo A, Vigano-D'Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-25.
52. Taylor FB, Stearns-Kurosawa DJ, Kurosawa S, Ferrell G, Chang ACK, Laszik Z, Kosanke S, Peer G, Esmon CT. The endothelial cell protein C receptor aids in host defense against Escherichia coli sepsis. Blood 2000; 95: 1680-6.
53. Lyseng-Williamson KA, Perry CM. Drotrecogin Alfa (Activated). Drugs 2002; 62: 617-30.
54. Fijen JW, Zijlstra JG, De Boer P, Spanjersberg R, Cohen-Tervaert JW, Van Der Werf TS, Ligtenberg JJ, Tulleken JE. Suppression of the clinical and cytokine response to endotoxin by RWJ-67657, a p38 mitogen-activated protein-kinase inhibitor, in healthy human volunteers. Clin Exp Immunol 2001; 124: 16-20.
55. Wischmeyer PE, Kahana M, Wolfson R, Ren H, Musch MM, Chang EB. Glutamine reduces cytokine release, organ damage, and mortality in a rat model of endotoxemia. Shock 2001; 16: 398-402.
56. Fisher CJ, Opal SM, Lowry SF, Sadoff JC, LaBrecque JF, Donovan HC, Lookabaugh JL, Lemke J, Pribble JP, Stromatt SC. Role of interleukin-1 and the therapeutic potential of interleukin-1 receptor antagonist in sepsis. Circ Shock 1994; 44: 1-8.
57. Morinelli TA, Webb JG, Jaffa AA, Privitera PJ, Margolius HS. A metabolic fragment of bradykinin, Arg-Pro-Pro-Gly-Phe, protects against the deleterious effects of lipopolysaccharide in rats. J Pharmacol Exp Ther 2001; 296: 71-6.
58. Satriano J, Schwartz D, Ishizuka S, Lortie MJ, Thomson SC, Gabbai F, Kelly CJ, Blantz RC. Suppression of inducible nitric oxide generation by agmatine aldehyde: Beneficial effects in sepsis. J Cell Physiol 2001; 188: 313-20.
59. Ramani M, Ollivier V, Khechai F, Vu T, Ternisien C, Bridey F, de Prost D. Interleukin-10 inhibits endotoxin-induced tissue factor mRNA production by human monocytes. FEBS Lett 1993; 334: 114-6.
60. Kahlke V, Dohm C, Mees T, Brotzmann K, Schreiber S, Schroder J. Early interleukin-10 treatment improves survival and enhances immune function only in males after hemorrhage and subsequent sepsis. Shock 2002; 18: 24-8.
61. Latifi SQ, O'Riordan MA, Levine AD. Interleukin-10 controls the onset of irreversible septic shock. Infect Immun 2002; 70: 4441-6.
62. Levi M. Pathogenesis and treatment of disseminated intravascular coagulation in the septic patient. J Crit Care 2001; 16: 167-77.
63. Lehmann C, Taymoorian K, Wauer H, Krausch D, Birnbaum J, Kox WJ. Effects of the stable prostacyclin analogue iloprost on the plasma disappearance rate of indocyanine green in human septic shock. Intensive Care Med 2000; 26: 1557-60.
64. Kanji S, Devlin JW, Piekos KA, Racine E. Recombinant human activated protein C, drotrecogin alfa (activated): A novel therapy for severe sepsis. Pharmacotherapy 2001; 21: 1389-402.
65. Lay AJ, Donahue D, Tsai MJ, Castellino FJ. Acute inflammation is exacerbated in mice genetically predisposed to a severe protein C deficiency. Blood 2007; 109: 1984-91.
66. Mosnier LO, Zampolli A, Kerschen EJ, Schuepbach RA, Banerjee Y, Fernandez JA, Yang XV, Riewald M, Weiler H, Ruggeri ZM, Griffin JH. Hyper-antithrombotic, non-cytoprotective Glu149Ala-activated protein C mutant. Blood 2009: DOI: 10.1182/blood-2008-10-183327.
67. Elphick GF, Sarangi PP, Hyun YM, Hollenbaugh JA, Ayala A, Biffl WL, Chung HL, Rezaie AR, McGrath JL, Topham DJ, Reichner JS, Kim M. Recombinant human activated protein C inhibits integrin-mediated neutrophil migration. Blood 2009: DOI: 10.1182/blood-2008-09-180968
68. Scaldaferri F, Sans M, Vetrano S, Graziani C, De Cristofaro R, Gerlitz B, Repici A, Arena V, Malesci A, Panes J, Grinnell BW, Danese S. Crucial role of the protein C pathway in governing microvascular inflammation in inflammatory bowel disease. J Clin Invest 2007; 117: 1951-60.
69. Boehme M, Autschbach F, Zuna I, Scherbaum WA, Stange E, Raeth U, Sieg A, Stremmel W. Elevated serum levels and reduced immunohistochemical expression of thrombomodulin in active ulcerative colitis. Gastroenterology 1997; 113: 107-17.
70. Faioni EM, Ferrero S, Fontana G, Gianelli U, Ciulla MM, Vecchi M, Saibeni S, Biguzzi E, Cordani N, Franchi F, Bosari S, Cattaneo M. Expression of endothelial protein C receptor and thrombomodulin in the intestinal tissue of patients with inflammatory bowel disease. Crit Care Med 2004; 32: S266-70.
71. Lust M, Vulcano M, Danese S. The protein C pathway in inflammatory bowel disease: The missing link between inflammation and coagulation. Trends Mol Med 2008; 14: 237-44.
72. Vergnolle N, Cellars L, Mencarelli A, Rizzo G, Swaminathan S, Beck P, Steinhoff M, Andrade-Gordon P, Bunnett NW, Hollenberg MD, Wallace JL, Cirino G, Fiorucci S. A role for proteinase-activated receptor-1 in inflammatory bowel diseases. J Clin Invest 2004; 114: 1444-56.
73. Simmonds RE, Lane DA. Structural and functional implications of the intron/exon organization of the human endothelial cell protein C/ activated protein C receptor (EPCR) gene: Comparison with the structure of CD1/major histocompatibility complex alpha1 and alpha2 domains. Blood 1999; 94: 632-41.
74. Faioni EM, Ferrero S, Fontana G. Endothelial protein C receptor is expressed by CD83+ dendritic cells in the human gut mucosa and is down-regulated by bacterial antigens on monocyte-derived dendritic cells. J Thromb Haemost 2005; 3: Abstract # P0086.
75. Usman F, Hassan A, Ahmad A. Arterial stroke with protein S deficiency in Pakistan. Rawal Med J 2007; 32: 205-7.
76. Macko RF, Amerisco SF, Gruber A, Griffin JH, Fernandez JA, Barndt R, Quismorio FP Jr, Weiner JM, Fisher M. Impairments of the protein C system and fibrinolysis in infection-associated stroke. Stroke 1996; 27: 2005-11.
77. Shibata M, Kumar SR, Amar A, Fernandez JA, Hofman F, Griffin JH, Zlokovic BV. Anti-inflammatory, anti-thrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001; 103: 1799-805.
78. Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV. Activated protein C blocks p53-mediated apoptosis in ischemic human brain and endothelium and is neuroprotective. Nat Med 2003; 9: 338-42.
79. Guo H, Liu D, Gelbard H, Cheng T, Insalaco R, Fernández JA, Griffin JH, Zlokovic BV. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004; 41: 563-72.
80. Liu D, Cheng T, Guo H, Fernández JA, Griffin JH, Song X, Zlokovic BV. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat Med 2004; 10: 1379-83.
81. Thiyagarajan M, Fernández JA, Lane SM, Griffin Jh, Zlokovic BV. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J Neurosci 2008; 28: 12788-97.
82. Deane R, LaRue B, Sagare AP, Castellino FJ, Zhong Z, Zlokovic BV. Endothelial protein C receptor-assisted transport of activated protein C across the mouse blood-brain barrier. J Cereb Blood Flow Metab 2009; 29: 25-33.