Cytoprotective protein C pathways and implications for stroke and neurological disorders

Trends in Neurosciences

Volumn 34, Issue 4, 2011, Pages 198-209

  Zlokovic, Berislav V ^a   Griffin, John H ^b  

^a UNIVERSITY OF ROCHESTER MEDICAL CENTER   (United States)

^b SCRIPPS RESEARCH INSTITUTE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ACTIVATED PROTEIN C; PROTEIN C; PROTEINASE ACTIVATED RECEPTOR;

ASTROCYTE; BLOOD BRAIN BARRIER; BRAIN ISCHEMIA; CELL PROTECTION; DISEASE ASSOCIATION; DRUG ACTIVITY; DRUG MECHANISM; ENDOTHELIUM CELL; HUMAN; INTRACELLULAR SIGNALING; MICROGLIA; MIDDLE CEREBRAL ARTERY; MIDDLE CEREBRAL ARTERY OCCLUSION; MULTIPLE SCLEROSIS; NERVE INJURY; NEUROLOGIC DISEASE; NEUROPROTECTION; NONHUMAN; PERICYTE; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION; STROKE;

ANIMALS; BLOOD-BRAIN BARRIER; CLINICAL TRIALS AS TOPIC; CYTOPROTECTION; HUMANS; INFLAMMATION; MODELS, MOLECULAR; NERVE DEGENERATION; NERVOUS SYSTEM DISEASES; PROTEIN C; PROTEIN CONFORMATION; SIGNAL TRANSDUCTION; STROKE;

EID: 79953161072     PISSN: 01662236     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tins.2011.01.005     Document Type: Review

References (107)

1. Moskowitz M.A., et al. The science of stroke: mechanisms in search of treatments. Neuron 2010, 67:181-198.
2. Guo S., Lo E.H. Dysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke 2009, 40:S4-S7.
3. Zlokovic B.V. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron 2008, 57:178-201.
4. Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol. 2010, 120:287-296.
5. Zlokovic B.V. Neurodegeneration: are we overlooking the role of neurovascular unit?. Nat. Med. 2010, 16:1370-1371.
6. Boillée S., et al. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 2006, 52:39-59.
7. Alexandrov A.V. Current and future recanalization strategies for acute ischemic stroke. J. Intern. Med. 2010, 267:209-219.
8. Lees K.R., et al. Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 2010, 375:1695-1703.
9. Nogueira R.G., et al. Endovascular approaches to acute stroke, part 1: drugs, devices, and data. AJNR Am. J. Neuroradiol. 2009, 30:649-661.
10. Arai K., et al. Brain angiogenesis in developmental and pathological processes: neurovascular injury and angiogenic recovery after stroke. FEBS J. 2009, 276:4644-4652.
11. Cramer S.C., Riley J.D. Neuroplasticity and brain repair after stroke. Curr. Opin. Neurol. 2008, 21:76-82.
12. Tymianski M. Can molecular and cellular neuroprotection be translated into therapies for patients? Yes, but not the way we tried it before. Stroke 2010, 41:S87-S90.
13. O'Collins V.E., et al. 1,026 experimental treatments in acute stroke. Ann. Neurol. 2006, 59:467-477.
14. Shuaib A., et al. NXY-059 for the treatment of acute ischemic stroke. N. Eng. J. Med. 2007, 357:562-571.
15. Fisher M., et al. Enhancing the development and approval of acute stroke therapies: Stroke Therapy Academic Industry roundtable. Stroke 2005, 36:1808-1813.
16. Saver J.L., et al. Infarct volume as a surrogate or axilliary outcome measure in ischemic stroke clinical trials The RANTTAS Investigators. Stroke 1999, 30:293-298.
17. Johnston K.C., et al. Validation of an acute ischemic stroke model: does diffusion-weighted imaging lesion volume offer a clinically significant improvement in prediction of outcome?. Stroke 2007, 38:1820-1825.
18. Hand P.J., et al. MR diffusion-weighted imaging and outcome prediction after ischemic stroke. Neurology 2006, 66:1159-1163.
19. Feuerstein G.Z., et al. Missing steps in the STAIR case: a translational medicine perspective on the development of NXY-059 for treatment of acute ischemic stroke. J. Cereb. Blood Flow Metab. 2008, 28:217-219.
20. Stroke Therapy Academic Industry Roundtable (STAIR) Recommendations for standards regarding preclinical neuroprotective and restorative drug development. Stroke 1999, 30:2752-2758.
21. Saver J.L., et al. Stroke Therapy Academic Industry Roundtable (STAIR) recommendations for extended window acute stroke therapy trials. Stroke 2009, 40:2594-2600.
22. Marchesi V.T. Alzheimer's dementia begins as a disease of small blood vessels, damaged by oxidative-induced inflammation and dysregulated amyloid metabolism: implications for early detection and therapy. FASEB J. 2011, 25:5-13.
23. Boillée S., et al. Onset and progression in inherited ALS determined by motor neurons and microglia. Science 2006, 312:1389-1392.
24. Yamanaka K., et al. Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat. Neurosci. 2008, 11:251-253.
25. Zhong Z., et al. ALS-causing SOD1 mutants generate vascular changes prior to motor neuron degeneration. Nat. Neurosci. 2008, 11:420-422.
26. Armulik A., et al. Pericytes regulate the blood-brain barrier. Nature 2010, 468:557-561.
27. Bell R.D., et al. Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 2010, 68:409-427.
28. Mosnier L.O., et al. The cytoprotective protein C pathway. Blood 2007, 109:3161-3172.
29. Griffin J.H., et al. Activated protein C: potential therapy for severe sepsis, thrombosis, and stroke. Semin. Hematol. 2002, 39:197-205.
30. Griffin J.H., et al. The promise of protein C. Blood Cells Mol. Dis. 2006, 36:211-216.
31. Esmon C.T. Inflammation and the activated protein C anticoagulant pathway. Semin. Thromb. Hemost. 2006, 32(Suppl. 1):49-60.
32. Danese S., et al. The protein C pathway in tissue inflammation and injury: pathogenic role and therapeutic implications. Blood 2010, 115:1121-1130.
33. Rezaie A.R. Regulation of the protein C anticoagulant and anti-inflammatory pathways. Curr. Med. Chem. 2010, 17:2059-2069.
34. Yamamoto K., Loskutoff D.J. Extrahepatic expression and regulation of protein C in the mouse. Am. J. Pathol. 1998, 153:547-555.
35. Deane R., et al. 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.
36. Zhong Z., et al. Activated protein C therapy slows ALS-like disease in mice by transcriptionally inhibiting SOD1 in motor neurons and microglia cells. J. Clin. Invest. 2009, 119:3437-3449.
37. Esmon C.T., Glass J.D. The APCs of neuroprotection. J. Clin. Invest. 2009, 119:3205-3207.
38. Gale A.J., et al. 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.
39. Mosnier L.O., et al. Activated protein C variants with normal cytoprotective but reduced anticoagulant activity. Blood 2004, 104:1740-1744.
40. Mosnier L.O., et al. Activated protein C mutant with minimal anticoagulant activity, normal cytoprotective activity, and preservation of thrombin activatable fibrinolysis inhibitor-dependent cytoprotective functions. J. Biol. Chem. 2007, 282:33022-33033.
41. Bae J.S., et al. 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. 2007, 282:9251-9259.
42. Guo H., et al. Neuroprotective activities of activated protein C mutant with reduced anticoagulant activity. Eur. J. Neurosci. 2009, 29:1119-1130.
43. Wang Y., et al. Differential neuroprotection and risk for bleeding from activated protein C with varying degrees of anticoagulant activity. Stroke 2009, 40:1864-1869.
44. Walker C.T., et al. Activated protein C analog with reduced anticoagulant activity improves functional recovery and reduces bleeding risk following controlled cortical impact. Brain Res. 2010, 1347C:125-131.
45. Kerschen E.J., et al. Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J. Exp. Med. 2007, 204:2439-2448.
46. Mosnier L.O., et al. Hyperantithrombotic, noncytoprotective Glu149Ala-activated protein C mutant. Blood 2009, 113:5970-5978.
47. Joyce D.E., Grinnell B.W. Recombinant human activated protein C attenuates the inflammatory response in endothelium and monocytes by modulating nuclear factor-kappaB. Crit. Care Med. 2002, 30:S288-S293.
48. Riewald M., et al. Activation of endothelial cell protease activated receptor 1 by the protein C pathway. Science 2002, 296:1880-1882.
49. Cheng T., et al. Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat. Med. 2003, 9:338-342.
50. Dömötör E., et al. 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, 101:4797-4801.
51. Mosnier L.O., Griffin J.H. 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.
52. 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.
53. Finigan J.H., et al. Activated protein C mediates novel lung endothelial barrier enhancement: role of sphingosine 1-phosphate receptor transactivation. J. Biol. Chem. 2005, 280:17286-17293.
54. Cheng T., et al. Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat. Med. 2006, 12:1278-1285.
55. Guo H., et al. Activated protein C prevents neuronal apoptosis via protease activated receptors 1 and 3. Neuron 2004, 41:563-572.
56. Shibata M., et al. Anti-inflammatory, antithrombotic, and neuroprotective effects of activated protein C in a murine model of focal ischemic stroke. Circulation 2001, 103:1799-1805.
57. Vu T.K., et al. Domains specifying thrombin-receptor interaction. Nature 1991, 353:674-677.
58. Coughlin S.R. Thrombin signalling and protease-activated receptors. Nature 2000, 407:258-264.
59. 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.
60. Yang L., et al. Identification of a specific exosite on activated protein C for interaction with protease-activated receptor 1. J. Biol. Chem. 2007, 282:25493-25500.
61. Gardell S.E., et al. Emerging medicinal roles for lysophospholipid signaling. Trends Mol. Med. 2006, 12:65-75.
62. Liu D., et al. Tissue plasminogen activator neurovascular toxicity is controlled by activated protein C. Nat. Med. 2004, 10:1379-1383.
63. Uchiba M., et al. Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo. Circ. Res. 2004, 95:34-41.
64. Thiyagarajan M., et al. Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease-activated receptor 1. J. Neurosci. 2008, 28:12788-12797.
65. Petraglia A.L., et al. Activated protein C is neuroprotective and mediates new blood vessel formation and neurogenesis after controlled cortical impact. Neurosurgery 2010, 66:165-171.
66. Gorbacheva L., et al. Activated protein C prevents glutamate- and thrombin-induced activation of nuclear factor-κB in cultured hippocampal neurons. Neuroscience 2010, 165:1138-1146.
67. Gorbacheva L., et al. 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.
68. Taoka Y., et al. Activated protein C reduces the severity of compression-induced spinal cord injury in rats by inhibiting activation of leukocytes. J. Neurosci. 1998, 18:1393-1398.
69. Mizutani A., et al. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 2000, 95:3781-3787.
70. Nick J.A., et al. Recombinant human activated protein C reduces human endotoxin-induced pulmonary inflammation via inhibition of neutrophil chemotaxis. Blood 2004, 104:3878-3885.
71. Cao C., et al. The efficacy of activated protein C in murine endotoxemia is dependent on integrin CD11b. J. Clin. Invest. 2010, 120:1971-1980.
72. Kerschen E., et al. Activated protein C targets CD8+ dendritic cells to reduce the mortality of endotoxemia in mice. J. Clin. Invest. 2010, 120:3167-3178.
73. Bernard G.R., et al. Efficacy and safety of recombinant human activated protein C for severe sepsis. N. Engl. J. Med. 2001, 344:699-709.
74. Short M.A., et al. From bench to bedside: a review of clinical trial development plan of drotrecogin alfa (activated). Curr. Med. Res. Opin. 2006, 22:2525-2540.
75. Zlokovic B.V., et al. Functional recovery after embolic stroke in rodents by activated protein C. Ann. Neurol. 2005, 58:474-477.
76. Yesilirmak D.C., et al. Effects of activated protein C on neonatal hypoxic ischemic brain injury. Brain Res. 2008, 1210:56-62.
77. Taylor F.B., et al. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the Baboon. J. Clin. Invest. 1987, 79:918-925.
78. Gruber A., et al. Inhibition of thrombus formation by activated recombinant protein C in a primate model of arterial thrombosis. Circulation 1990, 82:578-585.
79. Marder V.J., Novokhatny V. Direct fibrinolytic agents: biochemical attributes, preclinical foundation and clinical potential. J. Thromb. Haemost. 2009, 8:433-444.
80. Stewart D., et al. Distinct dose-dependent effects of plasmin and t-PA on coagulation and hemorrhage. Blood 2003, 101:3002-3007.
81. Jahan R., et al. Middle cerebral artery occlusion in the rabbit using selective angiography: application for assessment of thrombolysis. Stroke 2008, 39:1613-1615.
82. Marder V.J., et al. Thrombolysis with plasmin: implications for stroke treatment. Stroke 2010, 41:S45-S49.
83. Chen Z.L., Strickland S. Neuronal death in hippocampus is promoted by plasmin-catalyzed degradation of laminin. Cell 1997, 91:917-925.
84. Loubele S.T., et al. Activated protein C protects against myocardial ischemia/reperfusion injury via inhibition of apoptosis and inflammation. Arterioscler. Thromb. Vasc. Biol. 2009, 29:1087-1092.
85. Kuriyama N., et al. The cytoprotective effects of addition of activated protein C into preservation solution on small-for-size grafts in rats. Liver Transpl. 2009, 16:1-11.
86. Bir, et al. Cytoprotective-selective activated protein C attenuates P. aeruginosa-induced lung injury in mice. Am. J. Respir. Cell Mol. Biol. 2011, 10.1165/rcmb.2010-0397OC.
87. Iserman B., et al. Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat. Med. 2007, 13:1349-1358.
88. Hirose K., et al. Activated protein C reduces the ischemia/reperfusion-induced spinal cord injury in rats by inhibiting neutrophil activation. Ann. Surg. 2000, 232:272-280.
89. Yamauchi T., et al. Neuroprotective effects of activated protein C through induction of insulin-like growth factor-1 (IGF-1), IGF-1 receptor, and its downstream signal phosphorylated serine-threonine kinase after spinal cord ischemia in rabbits. Stroke 2006, 37:1081-1086.
90. Han M.H., et al. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets. Nature 2008, 451:1076-1081.
91. Kleindorfer D., et al. National US estimates of recombinant tissue plasminogen activator use: ICD-9 codes substantially underestimate. Stroke 2008, 39:924-928.
92. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997, 28:2109-2118. NINDS t-PA Stroke Study Group.
93. Carpenter C.R., et al. Thrombolytic therapy for acute ischemic stroke beyond three hours. J. Emerg. Med. 2011, 40:82-92.
94. Saver J.L., Levine S.R. Alteplase for ischaemic stroke - much sooner is much better. Lancet 2010, 375:1667-1668.
95. Savva G.M., et al. Epidemiological studies of the effect of stroke on incident dementia: a systematic review. Stroke 2010, 41:e41-e46.
96. Johnson V.E., et al. Traumatic brain injury and amyloid-beta pathology: a link to Alzheimer's disease?. Nat. Rev. Neurosci. 2010, 11:361-370.
97. Shlosberg D., et al. Blood-brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat. Rev. Neurol. 2010, 6:393-403.
98. Tolis C.M., Bullock M.R. Critical appraisal of neuroprotection trials in head injury: what have we learned?. NeuroRx 2004, 1:71-79.
99. Mangialasche F., et al. Alzheimer's disease: clinical trials and drug development. Lancet Neurol. 2010, 9:702-716.
100. Hardy J. The amyloid hypothesis for Alzheimer's disease: a critical reappraisal. J. Neurochem. 2009, 110:1129-1134.
101. Zlokovic B.V. Neurovascular mechanisms of Alzheimer's neurodegeneration. Trends Neurosci. 2005, 28:202-208.
102. Orrell R.W. Motor neuron disease: systematic reviews of treatment for ALS and SMA. Br. Med. Bull. 2010, 93:145-159.
103. Bensimon G., et al. A controlled trial of riluzole in amyotrophic lateral sclerosis. ALS/Riluzole Study Group. N. Engl. J. Med. 1994, 330:585-591.
104. Ilieva H., et al. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 2009, 187:761-772.
105. Pellequer J.L., et al. Three-dimensional model of coagulation factor Va bound to activated protein C. Thromb. Haemost. 2000, 84:849-857.
106. Mather T., et al. The 2.8Å crystal structure of Gla-domainless activated protein C. EMBO J. 1996, 15:6822-6831.
107. Sali A., Blundell T.L. Comparative protein modelling by satisfaction of spatial restraints. J. Mol. Biol. 1993, 234:779-815.