Advertisement

Biochemistry (Moscow)

, Volume 82, Issue 7, pp 778–790 | Cite as

A new concept of action of hemostatic proteases on inflammation, neurotoxicity, and tissue regeneration

  • L. R. Gorbacheva
  • E. V. Kiseleva
  • I. G. Savinkova
  • S. M. StrukovaEmail author
Review

Abstract

Key hemostatic serine proteases such as thrombin and activated protein C (APC) are signaling molecules controlling blood coagulation and inflammation, tissue regeneration, neurodegeneration, and some other processes. By interacting with protease-activated receptors (PARs), these enzymes cleave a receptor exodomain and liberate new amino acid sequence known as a tethered ligand, which then activates the initial receptor and induces multiple signaling pathways and cell responses. Among four PAR family members, APC and thrombin mainly act via PAR1, and they trigger divergent effects. APC is an anticoagulant with antiinflammatory and cytoprotective activity, whereas thrombin is a protease with procoagulant and proinflammatory effects. Hallmark features of APC-induced effects result from acting via different pathways: limited proteolysis of PAR1 localized in membrane caveolae with coreceptor (endothelial protein C receptor) as well as its targeted proteolytic action at a receptor exodomain site differing from the canonical thrombin cleavage site. Hence, a new noncanonical tethered PAR1 agonist peptide (PAR1-AP) is formed, whose effects are poorly investigated in inflammation, tissue regeneration, and neurotoxicity. In this review, a concept about a role of biased agonism in effects exerted by APC and PAR1-AP via PAR1 on cells involved in inflammation and related processes is developed. New evidence showing a role for a biased agonism in activating PAR1 both by APC and PAR1-AP as well as induction of antiinflammatory and cytoprotective cellular responses in experimental inflammation, wound healing, and excitotoxicity is presented. It seems that synthetic PAR1 peptide-agonists may compete with APC in controlling some inflammatory and neurodegenerative diseases.

Keywords

thrombin activated protein C protease-activated receptors biased agonism inflammation tissue regeneration 

Abbreviations

AP9

NPNDKYEPF amide (synthetic PAR1 agonist)

APC

activated protein C

BBB

blood–brain barrier

EC

endothelial cells

EPCR

endothelial protein C receptor

GPCR

G-protein-coupled receptors

IL

interleukin

MC

mast cells

PAR

protease-activated receptor

PAR1-AP

PAR1 agonist peptide

PC

protein C

rAPC

recombinant activated protein C

S1P1

sphingosine-1-phosphate receptor 1

TF

tissue factor

TNF

tumor necrosis factor

tPA

tissue plasminogen activator

TRAP

thrombin-receptor agonist peptide

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Thom, T., Haase, N., Rosamond, W., Howard, V. J., Rumsfeld, J., Manolio, T., Zheng, Z. J., Flegal, K., O’Donnell, C., Kittner, S., Lloyd-Jones, D., Goff, D. C., Jr., Hong, Y., Adams, R., Friday, G., Furie, K., Gorelick, P., Kissela, B., Marler, J., Meigs, J., Roger, V., Sidney, S., Sorlie, P., Steinberger, J., Wasserthiel-Smoller, S., Wilson, M., and Wolf, P. (2006) Heart disease and stroke statistics–2006 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee, Circulation, 113, 85–151.CrossRefGoogle Scholar
  2. 2.
    Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Blaha, M. J., Dai, S., Ford, E. S., Fox, C. S., Franco, S., Fullerton, H. J., Gillespie, C., Hailpern, S. M., Heit, J. A., Howard, V. J., Huffman, M. D., Judd, S. E., Kissela, B. M., Kittner, S. J., Lackland, D. T., Lichtman, J. H., Lisabeth, L. D., Mackey, R. H., Magid, D. J., Marcus, G. M., Marelli, A., Matchar, D. B., McGuire, D. K., Mohler, E. R., Moy, C. S., Mussolino, M. E., Neumar, R. W., Nichol, G., Pandey, D. K., Paynter, N. P., Reeves, M. J., Sorlie, P. D., Stein, J., Towfighi, A., Turan, T. N., Virani, S. S., Wong, N. D., Woo, D., and Turner, M. B. (2014) Executive summary: heart disease and stroke statistics–2014 update: a report from the American Heart Association, Circulation, 129, 28–292.CrossRefGoogle Scholar
  3. 3.
    Griffin, J. H., Zlokovic, B. V., and Mosnier, L. O. (2015) Activated protein C: biased for translation, Blood, 125, 2898–2907.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Mosnier, L. O., Zlokovic, B. V., and Griffin, J. H. (2007) The cytoprotective protein C pathway, Blood, 109, 3161–3172.CrossRefPubMedGoogle Scholar
  5. 5.
    Ramachandran, R., and Hollenberg, M. D. (2008) Proteinases and signalling: pathophysiological and therapeutic implications via PARs and more, Br. J. Pharmacol., 153, 263–282.CrossRefGoogle Scholar
  6. 6.
    Canto, I., Soh, U. J., and Trejo, J. (2012) Allosteric modulation of protease-activated receptor signaling, Mini Rev. Med. Chem., 12, 804–811.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Coughlin, S. R. (2000) Thrombin signalling and protease-activated receptors, Nature, 407, 258–264.CrossRefPubMedGoogle Scholar
  8. 8.
    Coughlin, S. R. (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology, Thromb. Haemost., 3, 1800–1814.CrossRefGoogle Scholar
  9. 9.
    Riewald, M., Petrovan, R. J., Donner, A., and Ruf, W. (2003) Activated protein C signals through the thrombin receptor PAR1 in endothelial cells, J. Endotoxin Res., 9, 317–321.CrossRefPubMedGoogle Scholar
  10. 10.
    Steinhoff, M., Buddenkotte, J., Shpacovitch, V., Rattenholl, A., Moormann, C., Vergnolle, N., Luger, T. A., and Hollenberg, M. D. (2005) Proteinase-activated receptors: transducers of proteinase-mediated signaling in inflammation and immune response, Endocr. Rev., 26, 1–43.CrossRefPubMedGoogle Scholar
  11. 11.
    Strukova, S. (2001) Thrombin as a regulator of inflammation and reparative processes in tissues, Biochemistry (Moscow), 66, 8–18.CrossRefGoogle Scholar
  12. 12.
    Strukova, S. (2006) Blood coagulation-dependent inflammation. Coagulation-dependent inflammation and inflammation-dependent thrombosis, Front. Biosci., 11, 59–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Russo, A., Soh, U. J., Paing, M. M., Arora, P., and Trejo, J. (2009) Caveolae are required for protease-selective signaling by protease-activated receptor-1, Proc. Natl. Acad. Sci. USA, 106, 6393–6397.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mosnier, L. O., Sinha, R. K., Burnier, L., Bouwens, E. A., and Griffin, J. H. (2012) Biased agonism of protease-activated receptor 1 by activated protein C caused by non-canonical cleavage at Arg46, Blood, 120, 5237–5246.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Esmon, C. T. (2005) The interactions between inflammation and coagulation, Br. J. Haematol., 131, 417–430.CrossRefPubMedGoogle Scholar
  16. 16.
    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.CrossRefPubMedGoogle Scholar
  17. 17.
    Jackson, C. J., and Xue, M. (2008) Activated protein C–an anticoagulant that does more than stop clots, Int. J. Biochem. Cell Biol., 40, 2692–2697.CrossRefPubMedGoogle Scholar
  18. 18.
    Schuepbach, R. A., Feistritzer, C., Fernandez, J. A., Griffin, J. H., and Riewald, M. (2009) Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1, Thromb. Haemost., 101, 724–733.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Gorbacheva, L. R., Storozhevykh, T. P., Pinelis, V. G., Davydova, O. N., Ishiwata, S., and Strukova, S. M. (2008) Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity, Biochemistry (Moscow), 73, 717–724.CrossRefGoogle Scholar
  20. 20.
    Thiyagarajan, M., Fernandez, J. A., Lane, S. M., Griffin, J. H., and Zlokovic, B. V. (2008) Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1, J. Neurosci., 28, 12788–12797.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    McKelvey, K., Jackson, C. J., and Xue, M. (2014) Activated protein C: a regulator of human skin epidermal keratinocyte function, World J. Biol. Chem., 5, 169–179.PubMedPubMedCentralGoogle Scholar
  22. 22.
    Kiseleva, E. V., Sidorova, M. V., Gorbacheva, L. R., and Strukova, S. M. (2014) Peptide-agonist of protease-activated receptor (PAR 1), similar to activated protein C, promotes proliferation in keratinocytes and wound healing of epithelial layer, Biomed. Khim., 60, 702–706.CrossRefPubMedGoogle Scholar
  23. 23.
    Danese, S., Vetrano, S., Zhang, L., Poplis, V. A., and Castellino, F. J. (2010) The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications, Blood, 115, 1121–1130.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Zlokovic, B. V., and Griffin, J. H. (2011) Cytoprotective protein C pathways and implications for stroke and neurological disorders, Trends Neurosci., 34, 198–209.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Christiaans, S. C., Wagener, B. M., Esmon, C. T., and Pittet, J. F. (2013) Protein C and acute inflammation: a clinical and biological perspective, J. Physiol. Lung Cell Mol. Physiol., 305, 455–466.CrossRefGoogle Scholar
  26. 26.
    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.CrossRefPubMedGoogle Scholar
  27. 27.
    Guo, H., Singh, I., Wang, Y., Deane, R., Barrett, T., Fernandez, J. A., Chow, N., Griffin, J. H., and Zlokovic, B. V. (2009) Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity, Eur. J. Neurosci., 29, 1119–1130.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Wang, Y., Zhao, Z., Chow, N., Rajput, P. S., Griffin, J. H., Lyden, P. D., and Zlokovic, B. V. (2013) Activated protein C analog protects from ischemic stroke and extends the therapeutic window of tissue-type plasminogen activator in aged female mice and hypertensive rats, Stroke, 44, 3529–3536.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Strukova, S. M. (2013) Basics of Hemostasis Physiology [in Russian], MGU Publishers, Moscow.Google Scholar
  30. 30.
    Monroe, D. M., and Hoffman, M. (2006) What does it take to make the perfect clot? Arterioscler. Thromb. Vasc. Biol., 26, 41–48.CrossRefPubMedGoogle Scholar
  31. 31.
    Engelmann, B., Luther, T., and Muller, I. (2003) Intravascular tissue factor pathway–a model for rapid initiation of coagulation within the blood vessel, Thromb. Haemost., 89, 3–8.PubMedGoogle Scholar
  32. 32.
    Butenas, S., and Mann, K. G. (2002) Blood coagulation, Biochemistry (Moscow), 67, 5–15.CrossRefGoogle Scholar
  33. 33.
    Versteeg, H. H., Heemskerk, J. W. M., Levi, M., and Reitsma, P. H. (2013) New fundamentals in hemostasis, Physiol. Rev., 93, 327–358.CrossRefPubMedGoogle Scholar
  34. 34.
    Esmon, C. T. (2002) Protein C pathway in sepsis, Ann. Med., 34, 598–605.CrossRefPubMedGoogle Scholar
  35. 35.
    Hollenberg, M. D., Mihara, K., Polley, D., Suen, J. Y., Han, A., Fairlie, D. P., and Ramachandran, R. (2014) Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease, Br. J. Pharmacol., 171, 1180–1194.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    El-Daly, M., Saifeddine, M., Mihara, K., Ramachandran, R., Triggle, C. R., and Hollenberg, M. D. (2014) Proteinase-activated receptors 1 and 2 and the regulation of porcine coronary artery contractility: a role for distinct tyrosine kinase pathways, Br. J. Pharmacol., 171, 2413–2425.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Vu, T., Hung, D., Wheaton, V., and Coughlin, S. (1991) Molecular cloning of a functional thrombin receptor reveals a novel proteolytic mechanism of receptor activation, Cell, 64, 1057–1068.CrossRefPubMedGoogle Scholar
  38. 38.
    McCoy, K. L., Gyoneva, S., Vellano, C. P., Smrcka, A. V., Traynelis, S. F., and Hepler, J. R. (2012) Protease-activated receptor 1 (PAR1) coupling to G(q/11) but not to G(i/o) or G(12/13) is mediated by discrete amino acids within the receptor second intracellular loop, Cell Signal., 24, 1351–1360CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Sokolova, E., and Reiser, G. (2008) Prothrombin/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases, Thromb. Haemost., 100, 576–581.PubMedGoogle Scholar
  40. 40.
    Gorbacheva, L., Davidova, O., Sokolova, E., Ishiwata, S., Pinelis, V., Strukova, S., and Reiser, G. (2009) Endothelial protein C receptor is expressed in rat cortical and hippocampal neurons and is necessary for protective effect of activated protein C at glutamate excitotoxicity, J. Neurochem., 111, 967–975CrossRefPubMedGoogle Scholar
  41. 41.
    Strukova, S. M., and Sereyskaya, A. A. (1988) On the two types of the thrombin high molecular substrates, Thromb. Res., 49, 303–304.CrossRefPubMedGoogle Scholar
  42. 42.
    Ramachandran, R., Noorbakhsh, F., Defea, K., and Hollenberg, M. D. (2012) Targeting proteinase-activated receptors: therapeutic potential and challenges, Nat. Rev. Drug Discov., 11, 69–86.CrossRefPubMedGoogle Scholar
  43. 43.
    Riewald, M., and Ruf, W. (2005) Protease-activated recep-tor-1 signaling by activated protein C in cytokine-perturbed endothelial cells is distinct from thrombin signaling, J. Biol. Chem., 280, 19808–19814.CrossRefPubMedGoogle Scholar
  44. 44.
    Russo, A., Soh, U. J., and Trejo, J. (2009) Proteases display biased agonism at protease-activated receptors: location matters! Mol. Interv., 9, 87–96.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Macfarlane, S. R., Seatter, M. J., Kanke, T., Hunter, G. D., and Plevin, R. (2001) Proteinase-activated receptors, Pharmacol. Rev., 53, 245–282.PubMedGoogle Scholar
  46. 46.
    Traynelis, S. F., and Trejo, J. (2007) Protease-activated receptor signaling: new roles and regulatory mechanisms, Curr. Opin. Hematol., 14, 230–235.CrossRefPubMedGoogle Scholar
  47. 47.
    Bae, J.-S., Yang, L., Manithody, C., and Rezaie, A. R. (2007) 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.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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.CrossRefPubMedGoogle Scholar
  49. 49.
    Feistritzer, C., and Riewald, M. (2005) Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor-1 cross-activation, Blood, 105, 3178–3184.CrossRefPubMedGoogle Scholar
  50. 50.
    Minhas, N., Xue, M., Fukudome, K., and Jackson, C. J. (2010) Activated protein C utilizes the angiopoietin/Tie2 axis to promote endothelial barrier function, FASEB J., 24, 873–881.CrossRefPubMedGoogle Scholar
  51. 51.
    Komarova, Y. A., Mehta, D., and Malik, A. B. (2007) Dual regulation of endothelial junctional permeability, Sci. STKE, 412, re8.Google Scholar
  52. 52.
    Bouwens, E. A. M., Stavenuiter, F., and Mosnier, L. O. (2013) Mechanisms of anticoagulant and cytoprotective actions of the protein C pathway, Thromb. Haemost., 11, 242–253.CrossRefGoogle Scholar
  53. 53.
    Rezaie, A. R. (2014) Protease-activated receptor signalling by coagulation proteases in endothelial cells, J. Thromb. Haemost., 112, 876–882.CrossRefGoogle Scholar
  54. 54.
    Soh, U. J., and Trejo, J. (2011) Activated protein C pro-motes protease-activated receptor-1 cytoprotective signaling through ß-arrestin and dishevelled-2 scaffolds, Proc. Natl. Acad. Sci. USA, 108, 1372–1380.CrossRefGoogle Scholar
  55. 55.
    Kovacs, J. J., Hara, M. R., Davenport, C. L., Kim, J., and Lefkowitz, R. J. (2009) Arrestin development: emerging roles for beta-arrestins in developmental signaling pathways, Dev. Cell, 17, 443–458.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Rajagopal, S., Rajagopal, K., and Lefkowitz, R. J. (2010) Teaching old receptors new tricks: biasing seven-transmembrane receptors, Nat. Rev. Drug Discov., 9, 373–386.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Shenoy, S. K., and Lefkowitz, R. J. (2011) ß-Arrestin-mediated receptor trafficking and signal transduction, Trends Pharmacol. Sci., 32, 521–533.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Whalen, E. J., Rajagopal, S., and Lefkowitz, R. J. (2011) Therapeutic potential of ß-arrestin-and G protein-biased agonists, Trends Mol. Med., 17, 126–139.CrossRefPubMedGoogle Scholar
  59. 59.
    Wisler, J. W., Xiao, K., Thomsen, A. R., and Lefkowitz, R. J. (2014) Recent developments in biased agonism, Curr. Opin. Cell Biol., 27, 18–24.CrossRefPubMedGoogle Scholar
  60. 60.
    Gieseler, F., Ungefroren, H., Settmacher, U., Hollenberg, M. D., and Kaufmann, R. (2013) Proteinase-activated receptors (PARs)–focus on receptor–receptor interactions and their physiological and pathophysiological impact, Cell Commun. Signal., 11,86.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Mosnier, L. O., Zlokovic, B. V., and Griffin, J. H. (2014) Cytoprotective-selective activated protein C therapy for ischaemic stroke, J. Thromb. Haemost., 112, 883–892.CrossRefGoogle Scholar
  62. 62.
    Bae, J. S., Yang, L., and Rezaie, A. R. (2007) 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.CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Bae, J. S., and Rezaie, A. R. (2008) Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein C receptor is occupied by its natural ligand, Thromb. Haemost., 100, 101–109.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Ossovskaya, V., and Bunnett, N. (2004) Protease-activated receptors: contribution to physiology and disease, Physiol. Rev., 84, 579–621.CrossRefPubMedGoogle Scholar
  65. 65.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Coughlin, S. R. (2001) Protease-activated receptors in vas-cular biology, J. Thromb. Haemost., 86, 298–307.Google Scholar
  67. 67.
    Guo, H., Zhao, Z., Yang, Q., Wang, M., Bell, R. D., Wang, S., Chow, N., Davis, T. P., Griffin, J. H., Goldman, S. A., and Zlokovic, B. V. (2013) An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway, J. Neurosci., 33, 6181–6190.CrossRefPubMedPubMedCentralGoogle Scholar
  68. 68.
    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., and Fisher, C. J. (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis, N. Engl. J. Med., 344, 699–709.CrossRefPubMedGoogle Scholar
  69. 69.
    Schouten, M., van’t Veer, C., Roelofs, J. J., Gerlitz, B., Grinnell, B. W., Levi, M., and Van der Poll, T. (2011) Recombinant activated protein C attenuates coagulopathy and inflammation when administered early in murine pneumococcal pneumonia, J. Thromb. Haemost., 106, 1189–1196.CrossRefGoogle Scholar
  70. 70.
    O’Brien, L. A., Gupta, A., and Grinnell, B. W. (2006) Activated protein C and sepsis, Front. Biosci., 11, 676–698.CrossRefPubMedGoogle Scholar
  71. 71.
    Gorbacheva, L. R., Storozhevykh, T. P., Pinelis, V. G., Ishiwata, S., and Strukova, S. M. (2006) Modulation of hippocampal neuron survival by thrombin and factor Xa, Biochemistry (Moscow), 71, 1082–1089.CrossRefGoogle Scholar
  72. 72.
    Makarova, A. M., Gorbacheva, L. R., Zamolodchikova, T. S., Rumsh, L. D., Bespalova, Z. D., and Strukova, S. M. (2008) Various effects of serine proteinases, activated protein C and duodenase on mast cells, Biomed. Khim., 54, 649–658.PubMedGoogle Scholar
  73. 73.
    Rusanova, A. V., Vasil’eva, T. V., Smirnov, M. D., and Strukova, S. M. (2009) Mast cells as a target for anti-inflammatory effects induced by activated protein C, Tsitokiny Vospalenie, 8, 48–53.Google Scholar
  74. 74.
    Teschendorf, P., Albertsmeier, M., Vogel, P., Padosch, S. A., Spohr, F., Kirschfink, M., Schwaninger, M., Bottiger, B. W., and Popp, E. (2008) Neurological outcome and inflammation after cardiac arrest–effects of protein C in rats, Resuscitation, 79, 316–324.CrossRefPubMedGoogle Scholar
  75. 75.
    Bruckner, M., Lasarzik, I., Jahn-Eimermacher, A., Peetz, D., Werner, C., Engelhard, K., and Thal, S. C. (2013) High dose infusion of activated protein C (rhAPC) fails to improve neuronal damage and cognitive deficit after global cerebral ischemia in rats, Neurosci. Lett., 13, 28–33.CrossRefGoogle Scholar
  76. 76.
    FDA Drug Safety Communication: Voluntary market with-drawal of Xigris [drotrecogin alfa (activated)] due to failure to show a survival benefit, http://www.fda.gov/Drugs/ DrugSafety/ucm277114.htmGoogle Scholar
  77. 77.
    Mosnier, L. O., Yang, X. V., and Griffin, J. H. (2007) Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cyto-protective functions, J. Biol. Chem., 282, 33022–33033.CrossRefPubMedGoogle Scholar
  78. 78.
    Adibhatla, R. M., and Hatcher, J. F. (2008) Tissue plasminogen activator (tPA) and matrix metalloproteinases in the pathogenesis of stroke: therapeutic strategies, CNS Neurol. Disord. Drug Targets, 7, 243–253.CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Loubele, S. T., Spronk, H. M., and Ten Cate, H. (2009) Activated protein C: a promising drug with multiple effects? Mini Rev. Med. Chem., 9, 620–626.CrossRefPubMedGoogle Scholar
  80. 80.
    Strbian, D., Kovanen, P. T., Karjalainen-Lindsberg, M.-L., Tatlisumak, T., and Lindsberg, P. J. (2009) An emerging role of mast cells in cerebral ischemia and hemorrhage, Ann. Med., 41, 438–450.CrossRefPubMedGoogle Scholar
  81. 81.
    Del Zoppo, G. J. (2009) Inflammation and the neurovascular unit in the setting of focal cerebral ischemia, Neuroscience, 158, 972–982.CrossRefPubMedGoogle Scholar
  82. 82.
    Lindsberg, P. J., Strbian, D., and Karjalainen-Lindsberg, M. L. (2010) Mast cells as early responders in the regulation of acute blood-brain barrier changes after cerebral ischemia and hemorrhage, J. Cereb. Blood Flow Metab., 30, 689–702.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Heikkila, H. M., Latti, S., Leskinen, M. J., Hakala, J. K., Kovanen, P. T., and Lindstedt, K. A. (2008) Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha, Arterioscler. Thromb. Vasc. Biol., 28, 309–314.CrossRefPubMedGoogle Scholar
  84. 84.
    Kovanen, P. T. (2009) Mast cells in atherogenesis: actions and reactions, Curr. Atheroscler. Rep., 11, 214–219.CrossRefPubMedGoogle Scholar
  85. 85.
    Dugina, T. N., Kiseleva, E. V., Glusa, E., and Strukova, S. M. (2003) Activation of mast cells induced by agonists of proteinase-activated receptors under normal conditions and during acute inflammation in rats, Eur. J. Pharmacol., 471, 141–147.CrossRefPubMedGoogle Scholar
  86. 86.
    Zhang, H., Zeng, X., and He, S. (2014) Evaluation on potential contributions of protease activated receptors related mediators in allergic inflammation, Mediat. Inflamm., doi: 10.1155/2014/829068.Google Scholar
  87. 87.
    Strukova, S., Piskunov, A., Rusanova, A., Gorbacheva, L., Ono, F., and Ishiwata, S. (2011) Activated protein C modulates mast cell functions and survival at inflammation, J. Thromb. Haemost., 9,598.Google Scholar
  88. 88.
    Shpacovitch, V., Feld, M., Hollenberg, M. D., Luger, T. A., and Steinhoff, M. (2008) Role of protease-activated receptors in inflammatory responses, innate and adaptive immunity, J. Leukoc. Biol., 83, 1309–1322.CrossRefPubMedGoogle Scholar
  89. 89.
    Tripathi, P., and Aggarwal, A. (2006) NF-κB transcription factor: a key player in the generation of immune response, Curr. Sci., 90, 519–531.Google Scholar
  90. 90.
    Joyce, D. E., Gelbert, L., Ciaccia, A., DeHoff, B., and Grinnell, B. W. (2001) Gene expression profile of antithrombotic protein C defines new mechanisms modu-lating inflammation and apoptosis, J. Biol. Chem., 276, 11199–11203.CrossRefPubMedGoogle Scholar
  91. 91.
    Gorbacheva, L., Pinelis, V., Ishiwata, S., Strukova, S., and Reiser, G. (2010) Activated protein C prevents glutamate-and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons, J. Neurosci., 165, 1138–1146.CrossRefGoogle Scholar
  92. 92.
    Savinkova, I. G., Gorbacheva, L. R., Bespalova, Z. D., Pinelis, V. G., and Strukova, S. M. (2014) Peptides analogous to tethered ligands liberated by activated protein C exert neuroprotective effects in glutamate-induced excitotoxicity, Biochemistry (Moscow), Suppl. Ser. A, 8, 116–120.Google Scholar
  93. 93.
    Ivanova, A. E., Gorbacheva, L. R., Strukova, S. M., Pinelis, V. G., and Reiser, G. (2014) Activated protein C and thrombin participate in the regulation of astrocyte functions, Biochemistry (Moscow), Suppl. Ser. A, 8, 50–59.Google Scholar
  94. 94.
    Jin, Y., Silverman, A. J., and Vannucci, S. J. (2007) Mast cell stabilization limits hypoxic-ischemic brain damage in the immature rat, Dev. Neurosci., 29, 373–384.CrossRefPubMedGoogle Scholar
  95. 95.
    Esposito, P., Gheorghe, D., Kandere, K., Pang, X., Connolly, R., Jacobson, S., and Theoharides, T. C. (2001) Acute stress increases permeability of the blood-brain-barrier through activation of brain mast cells, Brain Res., 888, 117–127.CrossRefPubMedGoogle Scholar
  96. 96.
    Babkina, I. I., Strukova, S. M., Pinelis, V. G., Reiser, G., and Gorbacheva, L. R. (2016) New synthetic peptide protects neurons from death induced by toxic influence of activated mast cells via protease-activated receptor, Biochemistry (Moscow), Suppl. Ser. A, 10, 126–134.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  • L. R. Gorbacheva
    • 1
    • 2
  • E. V. Kiseleva
    • 2
    • 3
  • I. G. Savinkova
    • 2
  • S. M. Strukova
    • 1
    Email author
  1. 1.Lomonosov Moscow State University, Faculty of BiologyMoscowRussia
  2. 2.Pirogov Russian National Research Medical UniversityMoscowRussia
  3. 3.Koltzov Institute of Developmental BiologyRussian Academy of SciencesMoscowRussia

Personalised recommendations