2016 Scientific Sessions Sol Sherry Distinguished Lecturer in Thrombosis: Thrombotic Stroke: Neuroprotective Therapy by Recombinant-Activated Protein C

Arteriosclerosis, Thrombosis, and Vascular Biology

Volumn 36, Issue 11, 2016, Pages 2143-2150

  Griffin, John H ^a,b   Mosnier, Laurent O ^a   Fernández, José A ^a   Zlokovic, Berislav V ^c  

^a SCRIPPS RESEARCH INSTITUTE   (United States)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

Author keywords

anticoagulant; endothelial cells; neurogenesis; neurons; stroke

Indexed keywords

DROTRECOGIN; PROTEIN C; PROTEINASE ACTIVATED RECEPTOR 1; TISSUE PLASMINOGEN ACTIVATOR; 3K3A-APC PROTEIN; CELL SURFACE RECEPTOR; LEUKOCYTE ANTIGEN; NEUROPROTECTIVE AGENT; PROCR PROTEIN, HUMAN; RECOMBINANT PROTEIN;

ANTICOAGULATION; BIOLOGICAL ACTIVITY; BLEEDING; BRAIN ISCHEMIA; HUMAN; NERVOUS SYSTEM DEVELOPMENT; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; ADVERSE EFFECTS; AGONISTS; ANIMAL; BRAIN; DRUG EFFECTS; ENDOTHELIUM CELL; FIBRINOLYTIC THERAPY; HEMOSTASIS; INTRACRANIAL THROMBOSIS; METABOLISM; NERVE CELL; PATHOLOGY; REPERFUSION INJURY; STROKE;

ANIMALS; ANTIGENS, CD; BRAIN; BRAIN ISCHEMIA; ENDOTHELIAL CELLS; HEMOSTASIS; HUMANS; INTRACRANIAL THROMBOSIS; NEUROGENESIS; NEURONS; NEUROPROTECTIVE AGENTS; PROTEIN C; RECEPTOR CROSS-TALK; RECEPTOR, PAR-1; RECEPTORS, CELL SURFACE; RECOMBINANT PROTEINS; REPERFUSION INJURY; SIGNAL TRANSDUCTION; STROKE; THROMBOLYTIC THERAPY;

EID: 84991511007     PISSN: 10795642     EISSN: 15244636     Source Type: Journal    
DOI: 10.1161/ATVBAHA.116.308038     Document Type: Review

References (76)

1. Zerna C, Hegedus J, Hill MD. Evolving treatments for acute ischemic stroke. Circ Res. 2016; 118: 1425-1442. doi: 10.1161/ CIRCRESAHA.116.307005.
2. Amar AP, Griffin JH, Zlokovic BV. Combined neurothrombectomy or thrombolysis with adjunctive delivery of 3K3A-activated protein C in acute ischemic stroke. Front Cell Neurosci. 2015; 9: 344. doi: 10.3389/ fncel.2015.00344.
3. Campbell BC, Donnan GA, Lees KR, Hacke W, Khatri P, Hill MD, Goyal M, Mitchell PJ, Saver JL, Diener HC, Davis SM. Endovascular stent thrombectomy: the new standard of care for large vessel ischaemic stroke. Lancet Neurol. 2015; 14: 846-854. doi: 10.1016/S1474-4422(15)00140-4.
4. Marshall RS. Progress in intravenous thrombolytic therapy for acute stroke. JAMA Neurol. 2015; 72: 928-934. doi: 10.1001/jamaneurol.2015.0835.
5. Prabhakaran S, Ruff I, Bernstein RA. Acute stroke intervention: a systematic review. JAMA. 2015; 313: 1451-1462. doi: 10.1001/jama.2015.3058.
6. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2014: CD000213.
7. Chamorro Á, Dirnagl U, Urra X, Planas AM. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol. 2016; 15: 869-881. doi: 10.1016/ S1474-4422(16)00114-9.
8. Bai J, Lyden PD. Revisiting cerebral postischemic reperfusion injury: new insights in understanding reperfusion failure, hemorrhage, and edema. Int J Stroke. 2015; 10: 143-152. doi: 10.1111/ijs.12434.
9. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab. 2014; 34: 1573-1584. doi: 10.1038/jcbfm.2014.130.
10. Niego B, Medcalf RL. Plasmin-dependent modulation of the blood-brain barrier: a major consideration during tPA-induced thrombolysis? J Cereb Blood Flow Metab. 2014; 34: 1283-1296. doi: 10.1038/jcbfm.2014.99.
11. Zlokovic BV, Griffin JH. Cytoprotective protein C pathways and implications for stroke and neurological disorders. Trends Neurosci. 2011; 34: 198-209. doi: 10.1016/j.tins.2011.01.005.
12. O'Collins VE, Macleod MR, Donnan GA, Horky LL, van der Worp BH, Howells DW. 1, 026 experimental treatments in acute stroke. Ann Neurol. 2006; 59: 467-477. doi: 10.1002/ana.20741.
13. Howells DW, Sena ES, O'Collins V, Macleod MR. Improving the efficiency of the development of drugs for stroke. Int J Stroke. 2012; 7: 371-377. doi: 10.1111/j.1747-4949.2012.00805.x.
14. Kikuchi K, Tanaka E, Murai Y, Tancharoen S. Clinical trials in acute ischemic stroke. CNS Drugs. 2014; 28: 929-938. doi: 10.1007/ s40263-014-0199-6.
15. Mosnier LO, Zlokovic BV, Griffin JH. The cytoprotective protein C pathway. Blood. 2007; 109: 3161-3172. doi: 10.1182/blood-2006-09-003004.
16. Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C: biased for translation. Blood. 2015; 125: 2898-2907. doi: 10.1182/blood-2015-02-355974.
17. Esmon CT. Protein C anticoagulant system-anti-inflammatory effects. Semin Immunopathol. 2012; 34: 127-132. doi: 10.1007/ s00281-011-0284-6.
18. McKelvey K, Jackson CJ, Xue M. Activated protein C: a regulator of human skin epidermal keratinocyte function. World J Biol Chem. 2014; 5: 169-179. doi: 10.4331/wjbc.v5.i2.169.
19. Guo H, Zhao Z, Yang Q, Wang M, Bell RD, Wang S, Chow N, Davis TP, Griffin JH, Goldman SA, Zlokovic BV. An activated protein C analog stimulates neuronal production by human neural progenitor cells via a PAR1-PAR3-S1PR1-Akt pathway. J Neurosci. 2013; 33: 6181-6190. doi: 10.1523/JNEUROSCI.4491-12.2013.
20. Xue M, Chow SO, Dervish S, Chan YK, Julovi SM, Jackson CJ. Activated protein C enhances human keratinocyte barrier integrity via sequential activation of epidermal growth factor receptor and Tie2. J Biol Chem. 2011; 286: 6742-6750. doi: 10.1074/jbc.M110.181388.
21. Gupta A, Williams MD, Macias WL, Molitoris BA, Grinnell BW. Activated protein C and acute kidney injury: selective targeting of PAR-1. Curr Drug Targets. 2009; 10: 1212-1226.
22. Danese S, Vetrano S, Zhang L, Poplis VA, Castellino FJ. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood. 2010; 115: 1121-1130. doi: 10.1182/ blood-2009-09-201616.
23. Rezaie AR. The occupancy of endothelial protein C receptor by its ligand modulates the par-1 dependent signaling specificity of coagulation proteases. IUBMB Life. 2011; 63: 390-396. doi: 10.1002/iub.447.
24. Feistritzer C, Riewald M. Endothelial barrier protection by activated protein C through PAR1-dependent sphingosine 1-phosphate receptor- 1 crossactivation. Blood. 2005; 105: 3178-3184. doi: 10.1182/ blood-2004-10-3985.
25. Finigan JH, Dudek SM, Singleton PA, Chiang ET, Jacobson JR, Camp SM, Ye SQ, Garcia JG. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J Biol Chem. 2005; 280: 17286-17293. doi: 10.1074/jbc. M412427200.
26. 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: 19808-19814. doi: 10.1074/jbc. M500747200.
27. Kerschen E, Hernandez I, Zogg M, Jia S, Hessner MJ, Fernandez JA, Griffin JH, Huettner CS, Castellino FJ, Weiler H. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J Clin Invest. 2010; 120: 3167-3178. doi: 10.1172/JCI42629.
28. Gale AJ, Tsavaler A, Griffin JH. Molecular characterization of an extended binding site for coagulation factor Va in the positive exosite of activated protein C. J Biol Chem. 2002; 277: 28836-28840. doi: 10.1074/ jbc.M204363200.
29. Pellequer JL, Gale AJ, Getzoff ED, Griffin JH. Three-dimensional model of coagulation factor Va bound to activated protein C. Thromb Haemost. 2000: 84: 849-857.
30. Macko RF, Ameriso 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: 2005-2011.
31. Macko RF, Killewich LA, Fernández JA, Cox DK, Gruber A, Griffin JH. Brain-specific protein C activation during carotid artery occlusion in humans. Stroke. 1999; 30: 542-545.
32. Folsom AR, Rosamond WD, Shahar E, Cooper LS, Aleksic N, Nieto FJ, Rasmussen ML, Wu KK. Prospective study of markers of hemostatic function with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation. 1999; 100: 736-742.
33. Shibata M, Kumar SR, Amar A, Fernandez JA, Hofman F, Griffin JH, Zlokovic BV. Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation. 2001; 103: 1799-1805.
34. Fernández JA, Xu X, Liu D, Zlokovic BV, Griffin JH. Recombinant murine-activated protein C is neuroprotective in a murine ischemic stroke model. Blood Cells Mol Dis. 2003; 30: 271-276.
35. Griffin JH, Fernández JA, Lyden PD, Zlokovic BV. Activated protein C promotes neuroprotection: mechanisms and translation to the clinic. Thromb Res. 2016; 141(suppl 2): S62-S64. doi: 10.1016/S0049-3848(16)30368-1.
36. Cheng T, Liu D, Griffin JH, Fernandez 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: 338-342.
37. 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: 563-572.
38. Gorbacheva L, Davidova O, Sokolova E, Ishiwata S, Pinelis V, Strukova S, Reiser G. 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. 2009; 111: 967-975. doi: 10.1111/j.1471-4159.2009.06380.x.
39. Gorbacheva L, Pinelis V, Ishiwata S, Strukova S, Reiser G. Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-kappaB in cultured hippocampal neurons. Neuroscience. 2010; 165: 1138-1146. doi: 10.1016/j.neuroscience.2009.11.027.
40. Gorbacheva L, Strukova S, Pinelis V, Ishiwata S, Stricker R, Reiser G. NF-κB-dependent and -independent pathways in the protective effects of activated protein C in hippocampal and cortical neurons at excitotoxicity. Neurochem Int. 2013; 63: 101-111. doi: 10.1016/j.neuint.2013.05.008.
41. Gorbacheva LR, Storozhevykh TP, Pinelis VG, Davydova ON, Ishiwata S, Strukova SM. Activated protein C via PAR1 receptor regulates survival of neurons under conditions of glutamate excitotoxicity. Biochemistry (Mosc). 2008; 73: 717-724.
42. Gorbacheva LR, Storozhevykh TP, Pinelis VG, Ishiwata S, Strukova SM. Protease-activated receptor (PAR)1-mediated anti-apoptotic effect of activated protein C on glutamate excitotoxicity in hippocampal neurons. Thromb Haemost. 2007; 98: 1150-1152.
43. 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: 1379-1383. doi: 10.1038/ nm1122.
44. Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernández JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV. Activated protein C inhibits tissue plasminogen activatorinduced brain hemorrhage. Nat Med. 2006; 12: 1278-1285. doi: 10.1038/ nm1498.
45. 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: 12788-12797. doi: 10.1523/JNEUROSCI.3485-08.2008.
46. Wang YZ, Z, Rege, S.V, Wang, M, Si, G, Zhou, Y, Wang, S, Griffin, JH, Goldman SA, Zlokovic, BV. 3K3A-APC stimulates post ischemic neuronal repair by human neuronal stem cells in mice. Nat Med. 2016; 22: 1050-1055. doi: 10.1038/nm.4154.
47. Mosnier LO, Gale AJ, Yegneswaran S, Griffin JH. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood. 2004; 104: 1740-1744. doi: 10.1182/blood-2004-01-0110.
48. Mosnier LO, Yang XV, Griffin JH. Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activable fibrinolysis inhibitor-dependent cytoprotective functions. J Biol Chem. 2007; 282: 33022-33033. doi: 10.1074/jbc.M705824200.
49. Mosnier LO, Zlokovic BV, Griffin JH. Cytoprotective-selective activated protein C therapy for ischaemic stroke. Thromb Haemost. 2014; 112: 883-892. doi: 10.1160/TH14-05-0448.
50. Walker CT, Marky AH, Petraglia AL, Ali T, Chow N, Zlokovic BV. Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact. Brain Res. 2010; 1347: 125-131. doi: 10.1016/j. brainres.2010.05.075.
51. Wang Y, Thiyagarajan M, Chow N, Singh I, Guo H, Davis TP, Zlokovic BV. Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. Stroke. 2009; 40: 1864-1869. doi: 10.1161/STROKEAHA.108.536680.
52. Wang Y, Zhang Z, Chow N, Davis TP, Griffin JH, Chopp M, Zlokovic BV. An activated protein C analog with reduced anticoagulant activity extends the therapeutic window of tissue plasminogen activator for ischemic stroke in rodents. Stroke. 2012; 43: 2444-2449. doi: 10.1161/ STROKEAHA.112.658997.
53. Wang Y, Zhao Z, Chow N, Ali T, Griffin JH, Zlokovic BV. Activated protein C analog promotes neurogenesis and improves neurological outcome after focal ischemic stroke in mice via protease activated receptor 1. Brain Res. 2013; 1507: 97-104. doi: 10.1016/j.brainres.2013.02.023.
54. Gleeson EM, Dichiara MG, Salicio A, Quinn LM, Drakeford C, Russell SE, Walsh PT, Orbe J, Hermida J, Smith OP, O'Donnell JS, Montes R, Preston RJ. Activated protein C β-glycoform promotes enhanced noncanonical PAR1 proteolysis and superior resistance to ischemic injury. Blood. 2015; 126: 915-919. doi: 10.1182/blood-2015-03-632877.
55. Andreou AP, Efthymiou M, Yu Y, Watts HR, Noormohamed FH, Ma D, Lane DA, Crawley JT. Protective effects of non-anticoagulant activated protein C variant (D36A/L38D/A39V) in a murine model of ischaemic stroke. PLoS One. 2015; 10: e0122410. doi: 10.1371/journal.pone.0122410.
56. 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: 1880-1882. doi: 10.1126/science.1071699.
57. 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(pt 1): 65-70. doi: 10.1042/BJ20030341.
58. Rezaie AR. Protease-activated receptor signalling by coagulation proteases in endothelial cells. Thromb Haemost. 2014; 112: 876-882. doi: 10.1160/TH14-02-0167.
59. Bock F, Shahzad K, Vergnolle N, Isermann B. Activated protein C based therapeutic strategies in chronic diseases. Thromb Haemost. 2014; 111: 610-617. doi: 10.1160/TH13-11-0967.
60. Griffin JH, Zlokovic BV, Mosnier LO. Protein C anticoagulant and cytoprotective pathways. Int J Hematol. 2012; 95: 333-345. doi: 10.1007/ s12185-012-1059-0.
61. Yang XV, Banerjee Y, Fernández JA, Deguchi H, Xu X, Mosnier LO, Urbanus RT, de Groot PG, White-Adams TC, McCarty OJ, Griffin JH. Activated protein C ligation of ApoER2 (LRP8) causes Dab1-dependent signaling in U937 cells. Proc Natl Acad Sci U S A. 2009; 106: 274-279. doi: 10.1073/pnas.0807594106.
62. Sinha RK, Yang XV, Fernández JA, Xu X, Mosnier LO, Griffin JH. Apolipoprotein E receptor 2 mediates activated protein C-induced endothelial Akt activation and endothelial barrier stabilization. Arterioscler Thromb Vasc Biol. 2016; 36: 518-524. doi: 10.1161/ATVBAHA.115.306795.
63. Coughlin SR. Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost. 2005; 3: 1800-1814. doi: 10.1111/j.1538-7836.2005.01377.x.
64. Mosnier LO, Sinha RK, Burnier L, Bouwens EA, Griffin JH. Biased agonism of protease-activated receptor 1 by activated protein C caused by noncanonical cleavage at Arg46. Blood. 2012; 120: 5237-5246. doi: 10.1182/blood-2012-08-452169.
65. Mosnier LO, Griffin JH. Non-canonical cleavage of protease activated receptor 1 (PAR1) by activated protein C provides novel insights into the repertoire of cytoprotective and proinflammatory PAR1 signaling Blood. 2011: 118: 534.
66. Hollenberg MD, Mihara K, Polley D, Suen JY, Han A, Fairlie DP, Ramachandran R. Biased signalling and proteinase-activated receptors (PARs): targeting inflammatory disease. Br J Pharmacol. 2014; 171: 1180-1194. doi: 10.1111/bph.12544.
67. Rajagopal S, Rajagopal K, Lefkowitz RJ. Teaching old receptors new tricks: biasing seven-transmembrane receptors. Nat Rev Drug Discov. 2010; 9: 373-386. doi: 10.1038/nrd3024.
68. Katritch V, Cherezov V, Stevens RC. Diversity and modularity of G protein- coupled receptor structures. Trends Pharmacol Sci. 2012; 33: 17-27. doi: 10.1016/j.tips.2011.09.003.
69. Soh UJ, Trejo J. Activated protein C promotes protease-activated receptor- 1 cytoprotective signaling through β-arrestin and dishevelled-2 scaffolds. Proc Natl Acad Sci U S A. 2011; 108: E1372-E1380. doi: 10.1073/ pnas.1112482108.
70. Wildhagen KC, Lutgens E, Loubele ST, ten Cate H, Nicolaes GA. The structure-function relationship of activated protein C. Lessons from natural and engineered mutations. Thromb Haemost. 2011; 106: 1034-1045. doi: 10.1160/TH11-08-0522.
71. Quinn LM, Drakeford C, O'Donnell JS, Preston RJ. Engineering activated protein C to maximize therapeutic efficacy. Biochem Soc Trans. 2015; 43: 691-695. doi: 10.1042/BST20140312.
72. Guo H, Singh I, Wang Y, Deane R, Barrett T, Fernández JA, Chow N, Griffin JH, Zlokovic BV. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur J Neurosci. 2009; 29: 1119-1130. doi: 10.1111/j.1460-9568.2009.06664.x.
73. Wang Y, Sinha RK, Mosnier LO, Griffin JH, Zlokovic BV. Neurotoxicity of the anticoagulant-selective E149A-activated protein C variant after focal ischemic stroke in mice. Blood Cells Mol Dis. 2013; 51: 104-108. doi: 10.1016/j.bcmd.2013.02.009.
74. Williams PD, Zlokovic BV, Griffin JH, Pryor KE, Davis TP. Preclinical safety and pharmacokinetic profile of 3K3A-APC, a novel, modified activated protein C for ischemic stroke. Curr Pharm Des. 2012; 18: 4215-4222.
75. Lyden P, Levy H, Weymer S, Pryor K, Kramer W, Griffin JH, Davis TP, Zlokovic B. Phase 1 safety, tolerability and pharmacokinetics of 3K3A-APC in healthy adult volunteers. Curr Pharm Des. 2013; 19: 7479-7485.
76. Wang Y, Zhao Z, Chow N, Rajput PS, Griffin JH, Lyden PD, Zlokovic BV. 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. 2013; 44: 3529-3536. doi: 10.1161/ STROKEAHA.113.003350.