title: Activated protein C: biased for translation.
abstract: The homeostatic blood protease, activated protein C (APC), can function as (1) an antithrombotic on the basis of inactivation of clotting factors Va and VIIIa; (2) a cytoprotective on the basis of endothelial barrier stabilization and anti-inflammatory and antiapoptotic actions; and (3) a regenerative on the basis of stimulation of neurogenesis, angiogenesis, and wound healing. Pharmacologic therapies using recombinant human and murine APCs indicate that APC provides effective acute or chronic therapies for a strikingly diverse range of preclinical injury models. APC reduces the damage caused by the following: ischemia/reperfusion in brain, heart, and kidney; pulmonary, kidney, and gastrointestinal inflammation; sepsis; Ebola virus; diabetes; and total lethal body radiation. For these beneficial effects, APC alters cell signaling networks and gene expression profiles by activating protease-activated receptors 1 and 3. APC's activation of these G protein-coupled receptors differs completely from thrombin's activation mechanism due to biased signaling via either G proteins or β-arrestin-2. To reduce APC-associated bleeding risk, APC variants were engineered to lack >90% anticoagulant activity but retain normal cell signaling. Such a neuroprotective variant, 3K3A-APC (Lys191-193Ala), has advanced to clinical trials for ischemic stroke. A rich data set of preclinical knowledge provides a solid foundation for potential translation of APC variants to future novel therapies.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA; Division of Hematology-Oncology, Department of Medicine, University of California, San Diego, San Diego, CA; and.
authors.forename: John H
authors.initials: JH
authors.lastname: Griffin
authors.affiliation: Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Berislav V
authors.initials: BV
authors.lastname: Zlokovic
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA;
authors.forename: Laurent O
authors.initials: LO
authors.lastname: Mosnier
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D019610:Cytoprotection; D006801:Humans; D011486:Protein C / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D011486:Protein C
references.citation: Blood. 1989 Feb 15;73(3):639-42
references.pmid: 2917194
references.citation: Am J Respir Cell Mol Biol. 2011 Sep;45(3):632-41
references.pmid: 21257925
references.citation: Nat Immunol. 2007 Dec;8(12):1303-12
references.pmid: 17965715
references.citation: PLoS One. 2012;7(8):e38738
references.pmid: 22916090
references.citation: J Clin Invest. 2010 Jun;120(6):1971-80
references.pmid: 20458145
references.citation: J Thromb Haemost. 2011 Jul;9(7):1308-17
references.pmid: 21535395
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5662-7
references.pmid: 17376866
references.citation: Circulation. 1990 Aug;82(2):578-85
references.pmid: 2372904
references.citation: Blood. 2009 Jun 4;113(23):5970-8
references.pmid: 19244160
references.citation: J Biol Chem. 2001 Apr 6;276(14):11199-203
references.pmid: 11278252
references.citation: Blood. 2005 Apr 15;105(8):3178-84
references.pmid: 15626732
references.citation: J Neurosci. 2008 Nov 26;28(48):12788-97
references.pmid: 19036971
references.citation: Neuron. 2004 Feb 19;41(4):563-72
references.pmid: 14980205
references.citation: PLoS One. 2013;8(1):e54942
references.pmid: 23372797
references.citation: Circulation. 2001 Apr 3;103(13):1799-805
references.pmid: 11282913
references.citation: J Clin Invest. 1987 Mar;79(3):918-25
references.pmid: 3102560
references.citation: Blood. 2012 Mar 22;119(12):2914-21
references.pmid: 22167755
references.citation: J Clin Invest. 2009 Nov;119(11):3437-49
references.pmid: 19841542
references.citation: Thromb Haemost. 2014 Apr 1;111(4):610-7
references.pmid: 24652581
references.citation: Vitam Horm. 2014;95:323-63
references.pmid: 24559924
references.citation: Thromb Haemost. 2014 Nov;112(5):876-82
references.pmid: 24990498
references.citation: World J Biol Chem. 2014 May 26;5(2):169-79
references.pmid: 24921007
references.citation: Nature. 2013 Jun 27;498(7455):502-5
references.pmid: 23739325
references.citation: Nat Med. 2007 Nov;13(11):1349-58
references.pmid: 17982464
references.citation: Blood. 2014 Nov 27;124(23):3480-9
references.pmid: 25320242
references.citation: J Clin Invest. 1998 Oct 15;102(8):1481-8
references.pmid: 9788960
references.citation: Nat Med. 2006 Nov;12(11):1278-85
references.pmid: 17072311
references.citation: Invest Ophthalmol Vis Sci. 2011 Feb;52(2):987-93
references.pmid: 20688738
references.citation: Proc Natl Acad Sci U S A. 2014 Mar 18;111(11):E1035-42
references.pmid: 24591593
references.citation: Liver Transpl. 2010 Jan;16(1):1-11
references.pmid: 20035525
references.citation: JAMA. 2001 Oct 17;286(15):1869-78
references.pmid: 11597289
references.citation: Int Wound J. 2015 Aug;12(4):422-7
references.pmid: 23848141
references.citation: J Biol Chem. 2005 May 20;280(20):19808-14
references.pmid: 15769747
references.citation: J Biol Chem. 2011 Feb 25;286(8):6742-50
references.pmid: 21173154
references.citation: Kidney Int. 2009 Oct;76(7):739-50
references.pmid: 19625989
references.citation: Mol Pharmacol. 2010 Jun;77(6):1005-15
references.pmid: 20215560
references.citation: Blood. 2007 Dec 1;110(12):3909-16
references.pmid: 17823308
references.citation: Blood. 2004 Sep 15;104(6):1740-4
references.pmid: 15178575
references.citation: Blood. 2010 Feb 11;115(6):1121-30
references.pmid: 20018912
references.citation: Nature. 2008 Feb 28;451(7182):1076-81
references.pmid: 18278032
references.citation: Blood. 2014 Sep 4;124(10):1553-62
references.pmid: 25049281
references.citation: J Exp Med. 2007 Oct 1;204(10):2439-48
references.pmid: 17893198
references.citation: Blood. 2007 Apr 15;109(8):3161-72
references.pmid: 17110453
references.citation: Coron Artery Dis. 2007 Feb;18(1):61-6
references.pmid: 17172932
references.citation: Arterioscler Thromb Vasc Biol. 2009 Jul;29(7):1087-92
references.pmid: 19372456
references.citation: IUBMB Life. 2011 Jun;63(6):390-6
references.pmid: 21438119
references.citation: J Thromb Haemost. 2013 Jun;11 Suppl 1:242-53
references.pmid: 23809128
references.citation: JAMA. 2003 Jul 9;290(2):238-47
references.pmid: 12851279
references.citation: Thromb Haemost. 2014 Nov;112(5):883-92
references.pmid: 25230930
references.citation: Blood. 1991 Jun 15;77(12):2641-8
references.pmid: 2043766
references.citation: Pharmacol Rev. 2013;65(4):1198-213
references.pmid: 24064459
references.citation: Trends Neurosci. 2011 Apr;34(4):198-209
references.pmid: 21353711
references.citation: J Thromb Haemost. 2012 Mar;10(3):337-46
references.pmid: 22236035
references.citation: N Engl J Med. 2012 May 31;366(22):2055-64
references.pmid: 22616830
references.citation: Diabetes. 2004 Nov;53(11):2804-14
references.pmid: 15504960
references.citation: Blood. 2008 Mar 1;111(5):2667-73
references.pmid: 18089851
references.citation: Curr Drug Targets. 2009 Dec;10(12):1212-26
references.pmid: 19715537
references.citation: Arch Dis Child. 2011 Nov;96(11):1066-71
references.pmid: 21233082
references.citation: J Biol Chem. 2005 Apr 29;280(17):17286-93
references.pmid: 15710622
references.citation: Nat Med. 2003 Mar;9(3):338-42
references.pmid: 12563316
references.citation: J Clin Invest. 1981 Nov;68(5):1370-3
references.pmid: 6895379
references.citation: Nat Med. 2012 Jul;18(7):1123-9
references.pmid: 22729286
references.citation: J Biol Chem. 2007 Mar 23;282(12):9251-9
references.pmid: 17255099
references.citation: Br J Pharmacol. 2014 Mar;171(5):1180-94
references.pmid: 24354792
references.citation: Science. 2002 Jun 7;296(5574):1880-2
references.pmid: 12052963
references.citation: J Korean Med Sci. 2010 Nov;25(11):1609-15
references.pmid: 21060750
references.citation: J Biol Chem. 2013 Nov 15;288(46):32979-90
references.pmid: 24052258
references.citation: Proc Natl Acad Sci U S A. 2009 Jan 6;106(1):274-9
references.pmid: 19116273
references.citation: J Cereb Blood Flow Metab. 2009 Jan;29(1):25-33
references.pmid: 18841163
references.citation: Mini Rev Med Chem. 2012 Aug;12(9):804-11
references.pmid: 22681248
references.citation: Blood. 2015 Feb 19;125(8):1339-48
references.pmid: 25575539
references.citation: Blood. 2012 Jan 19;119(3):874-83
references.pmid: 22117049
references.citation: J Biol Chem. 1994 Oct 21;269(42):26486-91
references.pmid: 7929370
references.citation: J Neurosci. 2013 Apr 3;33(14):6181-90
references.pmid: 23554499
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 13;108(50):E1372-80
references.pmid: 22106258
references.citation: J Clin Invest. 2010 Sep;120(9):3167-78
references.pmid: 20714108
references.citation: Biochem J. 2003 Jul 1;373(Pt 1):65-70
references.pmid: 12683950
references.citation: J Infect Dis. 2007 Nov 15;196 Suppl 2:S390-9
references.pmid: 17940975
references.citation: Semin Immunopathol. 2012 Jan;34(1):127-32
references.pmid: 21822632
references.citation: Brain Res. 2013 Apr 24;1507:97-104
references.pmid: 23438513
references.citation: J Clin Invest. 2007 Jul;117(7):1951-60
references.pmid: 17557119
references.citation: FASEB J. 2010 Mar;24(3):873-81
references.pmid: 19858095
references.citation: Blood. 2013 Jan 17;121(3):431-9
references.pmid: 23086754
references.citation: Curr Pharm Des. 2012;18(27):4215-22
references.pmid: 22632606
references.citation: Am J Physiol Lung Cell Mol Physiol. 2013 Oct 1;305(7):L455-66
references.pmid: 23911436
references.citation: Stroke. 2013 Dec;44(12):3529-36
references.pmid: 24159062
references.citation: N Engl J Med. 2001 Mar 8;344(10):699-709
references.pmid: 11236773
references.citation: Blood. 2012 Dec 20;120(26):5237-46
references.pmid: 23149848
references.citation: JAMA Ophthalmol. 2014 Mar;132(3):361-2
references.pmid: 24626830
references.citation: Semin Hematol. 2002 Jul;39(3):197-205
references.pmid: 12124682
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 20;104(8):2867-72
references.pmid: 17299037
references.citation: J Biol Chem. 1992 Jul 5;267(19):13146-9
references.pmid: 1320011
references.citation: J Immunol. 2000 Oct 15;165(8):4697-703
references.pmid: 11035113
references.citation: Stroke. 2012 Sep;43(9):2444-9
references.pmid: 22811462
references.citation: Neurosurgery. 2010 Jan;66(1):165-71; discussion 171-2
references.pmid: 20023547
references.citation: Blood. 2013 Aug 1;122(5):807-16
references.pmid: 23788139
references.citation: Cell. 1991 Mar 22;64(6):1057-68
references.pmid: 1672265
references.citation: Lancet Infect Dis. 2012 Sep;12(9):678-86
references.pmid: 22809883
references.citation: J Thromb Haemost. 2014 Nov;12(11):1921-7
references.pmid: 25069533
references.citation: Am J Respir Crit Care Med. 2008 Sep 15;178(6):618-23
references.pmid: 18565951
references.citation: Arch Dermatol. 2008 Nov;144(11):1479-83
references.pmid: 19015423
references.citation: J Biol Chem. 2007 Nov 9;282(45):33022-33
references.pmid: 17872949
references.citation: Nat Rev Drug Discov. 2010 May;9(5):373-86
references.pmid: 20431569
references.citation: Curr Pharm Des. 2013;19(42):7479-85
references.pmid: 24372304
references.citation: Trends Pharmacol Sci. 2012 Jan;33(1):17-27
references.pmid: 22032986
references.citation: J Thromb Haemost. 2008 Jun;6(6):995-1002
references.pmid: 18489431
references.citation: Blood. 2003 Jun 15;101(12):4797-801
references.pmid: 12586611
references.citation: Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6393-7
references.pmid: 19332793
references.citation: Proc Natl Acad Sci U S A. 2011 Dec 6;108(49):19830-5
references.pmid: 22109555
references.citation: Blood. 2013 Aug 1;122(5):842-51
references.pmid: 23741007
references.citation: Brain Res. 2010 Aug 6;1347:125-31
references.pmid: 20513369
references.citation: J Biol Chem. 2007 Aug 31;282(35):25493-500
references.pmid: 17580306
references.citation: J Biol Chem. 2012 May 11;287(20):16356-64
references.pmid: 22447930
references.citation: Lancet. 1983 Nov 19;2(8360):1165-8
references.pmid: 6139528
references.citation: Clin Hemorheol Microcirc. 2006;34(1-2):153-61
references.pmid: 16543631
references.citation: Neuroscience. 2010 Feb 17;165(4):1138-46
references.pmid: 19931359
references.citation: J Thromb Haemost. 2014 Jan;12(1):93-102
references.pmid: 24119206
references.citation: J Clin Invest. 2005 Jun;115(6):1552-61
references.pmid: 15902301