Semin Thromb Hemost 2011; 37(4): 349-354
DOI: 10.1055/s-0031-1276583
© Thieme Medical Publishers

Protein C Inhibitor

Joost C.M. Meijers1 , Heiko Herwald2
  • 1Departments of Vascular Medicine and Experimental Vascular Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
  • 2Department of Clinical Sciences, Section for Clinical and Experimental Infection Medicine, Lund University, Lund, Sweden
Further Information

Publication History

Publication Date:
30 July 2011 (online)

ABSTRACT

Protein C inhibitor (PCI) is a serine protease inhibitor and was originally identified as an inhibitor of activated protein C (APC). However, PCI is not specific for APC and also inhibits several proteases involved in coagulation, fibrinolysis, cancer, wound healing, and fertility. The biological function of PCI is unknown due to broad enzyme specificity, its wide tissue distribution, and the lack of a suitable animal model. This review highlights the specific roles of PCI in the areas of hemostasis and thrombosis and fertilization, and it also describes the latest information on the fascinating participation of the protein in intracellular processes, phospholipid binding, and killing of bacteria.

REFERENCES

  • 1 Suzuki K, Deyashiki J, Nishioka K et al.. Characterization of a cDNA for human protein C inhibitor. A new member of the plasma serine protease inhibitor superfamily.  J Biol Chem. 1987;  262 (2) 611-616
  • 2 Meijers J CM, Chung D W. Organization of the gene coding for human protein C inhibitor (plasminogen activator inhibitor-3). Assignment of the gene to chromosome 14.  J Biol Chem. 1991;  266 (23) 15028-15034
  • 3 Marlar R A, Griffin J H. Deficiency of protein C inhibitor in combined factor V/VIII deficiency disease.  J Clin Invest. 1980;  66 (5) 1186-1189
  • 4 Suzuki K, Nishioka J, Hashimoto S. Protein C inhibitor. Purification from human plasma and characterization.  J Biol Chem. 1983;  258 (1) 163-168
  • 5 Suzuki K, Nishioka J, Kusumoto H, Hashimoto S. Mechanism of inhibition of activated protein C by protein C inhibitor.  J Biochem. 1984;  95 (1) 187-195
  • 6 Meijers J CM, Kanters DHAJ, Vlooswijk R AA, van Erp H E, Hessing M, Bouma B N. Inactivation of human plasma kallikrein and factor XIa by protein C inhibitor.  Biochemistry. 1988;  27 (12) 4231-4237
  • 7 Rezaie A R, Cooper S T, Church F C, Esmon C T. Protein C inhibitor is a potent inhibitor of the thrombin-thrombomodulin complex.  J Biol Chem. 1995;  270 (43) 25336-25339
  • 8 Elisen MGML, von dem Borne P AK, Bouma B N, Meijers J CM. Protein C inhibitor acts as a procoagulant by inhibiting the thrombomodulin-induced activation of protein C in human plasma.  Blood. 1998;  91 (5) 1542-1547
  • 9 Stump D C, Thienpont M, Collen D. Purification and characterization of a novel inhibitor of urokinase from human urine. Quantitation and preliminary characterization in plasma.  J Biol Chem. 1986;  261 (27) 12759-12766
  • 10 Heeb M J, España F, Geiger M, Collen D, Stump D C, Griffin J H. Immunological identity of heparin-dependent plasma and urinary protein C inhibitor and plasminogen activator inhibitor-3.  J Biol Chem. 1987;  262 (33) 15813-15816
  • 11 Stief T W, Radtke K P, Heimburger N. Inhibition of urokinase by protein C-inhibitor (PCI). Evidence for identity of PCI and plasminogen activator inhibitor 3.  Biol Chem Hoppe Seyler. 1987;  368 (10) 1427-1433
  • 12 Mosnier L O, Elisen MGLM, Bouma B N, Meijers J CM. Protein C inhibitor regulates the thrombin-thrombomodulin complex in the up- and down regulation of TAFI activation.  Thromb Haemost. 2001;  86 (4) 1057-1064
  • 13 Hermans J M, Jones R, Stone S R. Rapid inhibition of the sperm protease acrosin by protein C inhibitor.  Biochemistry. 1994;  33 (18) 5440-5444
  • 14 Elisen MGLM, van Kooij R J, Nolte M A et al.. Protein C inhibitor may modulate human sperm-oocyte interactions.  Biol Reprod. 1998;  58 (3) 670-677
  • 15 Ecke S, Geiger M, Resch I et al.. Inhibition of tissue kallikrein by protein C inhibitor. Evidence for identity of protein C inhibitor with the kallikrein binding protein.  J Biol Chem. 1992;  267 (10) 7048-7052
  • 16 Luo L Y, Jiang W. Inhibition profiles of human tissue kallikreins by serine protease inhibitors.  Biol Chem. 2006;  387 (6) 813-816
  • 17 Hobson J P, Netzel-Arnett S, Szabo R et al.. Mouse DESC1 is located within a cluster of seven DESC1-like genes and encodes a type II transmembrane serine protease that forms serpin inhibitory complexes.  J Biol Chem. 2004;  279 (45) 46981-46994
  • 18 Szabo R, Netzel-Arnett S, Hobson J P, Antalis T M, Bugge T H. Matriptase-3 is a novel phylogenetically preserved membrane-anchored serine protease with broad serpin reactivity.  Biochem J. 2005;  390 (Pt 1) 231-242
  • 19 Cardin A D, Weintraub H JR. Molecular modeling of protein-glycosaminoglycan interactions.  Arteriosclerosis. 1989;  9 (1) 21-32
  • 20 Kuhn L A, Griffin J H, Fisher C L et al.. Elucidating the structural chemistry of glycosaminoglycan recognition by protein C inhibitor.  Proc Natl Acad Sci U S A. 1990;  87 (21) 8506-8510
  • 21 Pratt C W, Church F C. Heparin binding to protein C inhibitor.  J Biol Chem. 1992;  267 (13) 8789-8794
  • 22 Shirk R A, Elisen MGLM, Meijers J CM, Church F C. Role of the H helix in heparin binding to protein C inhibitor.  J Biol Chem. 1994;  269 (46) 28690-28695
  • 23 Elisen MGLM, Maseland M HH, Church F C, Bouma B N, Meijers J CM. Role of the A + helix in heparin binding to protein C inhibitor.  Thromb Haemost. 1996;  75 (5) 760-766
  • 24 Huntington J A, Kjellberg M, Stenflo J. Crystal structure of protein C inhibitor provides insights into hormone binding and heparin activation.  Structure. 2003;  11 (2) 205-215
  • 25 Li W, Adams T E, Kjellberg M, Stenflo J, Huntington J A. Structure of native protein C inhibitor provides insight into its multiple functions.  J Biol Chem. 2007;  282 (18) 13759-13768
  • 26 Li W, Adams T E, Nangalia J, Esmon C T, Huntington J A. Molecular basis of thrombin recognition by protein C inhibitor revealed by the 1.6-A structure of the heparin-bridged complex.  Proc Natl Acad Sci U S A. 2008;  105 (12) 4661-4666
  • 27 Huntington J A, Li W. Structural insights into the multiple functions of protein C inhibitor.  Cell Mol Life Sci. 2009;  66 (1) 113-121
  • 28 Jerabek I, Zechmeister-Machhart M, Binder B R, Geiger M. Binding of retinoic acid by the inhibitory serpin protein C inhibitor.  Eur J Biochem. 2001;  268 (22) 5989-5996
  • 29 Geiger M. Protein C inhibitor, a serpin with functions in- and outside vascular biology.  Thromb Haemost. 2007;  97 (3) 343-347
  • 30 Wakita T, Hayashi T, Yuasa H, Nishioka J, Kawamura J, Suzuki K. Molecular cloning, tissue distribution and androgen regulation of rat protein C inhibitor.  FEBS Lett. 1998;  429 (3) 263-268
  • 31 Wagenaar G TM, van Vuuren A JH, Girma M et al.. Characterization of transgenic mice that secrete functional human protein C inhibitor into the circulation.  Thromb Haemost. 2000;  83 (1) 93-101
  • 32 Uhrin P, Dewerchin M, Hilpert M et al.. Disruption of the protein C inhibitor gene results in impaired spermatogenesis and male infertility.  J Clin Invest. 2000;  106 (12) 1531-1539
  • 33 Wagenaar G TM, Uhrin P, Weipoltshammer K et al.. Expression patterns of protein C inhibitor in mouse development.  J Mol Histol. 2010;  41 (1) 27-37
  • 34 Hayashi T, Nishioka J, Nakagawa N et al.. Protein C inhibitor directly and potently inhibits activated hepatocyte growth factor activator.  J Thromb Haemost. 2007;  5 (7) 1477-1485
  • 35 España F, Vicente V, Tabernero D, Scharrer I, Griffin J H. Determination of plasma protein C inhibitor and of two activated protein C-inhibitor complexes in normals and in patients with intravascular coagulation and thrombotic disease.  Thromb Res. 1990;  59 (3) 593-608
  • 36 Tabernero D, España F, Vicente V, Estellés A, Gilabert J, Aznar J. Protein C inhibitor and other components of the protein C pathway in patients with acute deep vein thrombosis during heparin treatment.  Thromb Haemost. 1990;  63 (3) 380-382
  • 37 Minamikawa K, Wada H, Wakita Y et al.. Increased activated protein C-protein C inhibitor complex levels in patients with pulmonary embolism.  Thromb Haemost. 1994;  71 (2) 192-194
  • 38 Carroll V A, Griffiths M R, Geiger M et al.. Plasma protein C inhibitor is elevated in survivors of myocardial infarction.  Arterioscler Thromb Vasc Biol. 1997;  17 (1) 114-118
  • 39 Meijers J CM, Marquart J A, Bertina R M, Bouma B N, Rosendaal F R. Protein C inhibitor (plasminogen activator inhibitor-3) and the risk of venous thrombosis.  Br J Haematol. 2002;  118 (2) 604-609
  • 40 Strandberg K, Stenflo J, Nilsson C, Svensson P J. APC-PCI complex concentration is higher in patients with previous venous thromboembolism with factor V Leiden.  J Thromb Haemost. 2005;  3 (11) 2578-2580
  • 41 Strandberg K, Svensson P J, Ohlin A K. Venous thromboembolism in carriers of the factor V Leiden mutation and in patients without known thrombophilic risk factor; prediction of recurrence and APC-PCI complex concentration and/or soluble thrombomodulin antigen and activity.  Thromb Res. 2007;  121 (2) 145-151
  • 42 Kölbel T, Goncalves I, Dias N, Strandberg K, Acosta S, Gottsäter A. Coagulation activation and ultrasound characteristics in patients with carotid artery disease.  Thromb Res. 2010;  125 (2) 171-177
  • 43 Undén J, Strandberg K, Malm J et al.. Explorative investigation of biomarkers of brain damage and coagulation system activation in clinical stroke differentiation.  J Neurol. 2009;  256 (1) 72-77
  • 44 Nilsson G, Strandberg K, Astermark J, Vernersson E, Stenflo J, Berntorp E. The APC-PCI complex concentration predicts outcome of aortic surgery.  Thromb Res. 2007;  120 (2) 237-244
  • 45 Bakoush O, Ohlin A K, Strandberg K, Kurkus J. Low plasma activated protein C-protein C inhibitor complex concentration is associated with vascular access failure in hemodialysis patients.  Nephron Clin Pract. 2008;  110 (3) c151-c157
  • 46 Matsumoto K, Yano Y, Gabazza E C et al.. Inverse correlation between activated protein C generation and carotid atherosclerosis in type 2 diabetic patients.  Diabet Med. 2007;  24 (12) 1322-1328
  • 47 Blomstrand D, Kölbel T, Lindblad B, Gottsäter A. Activated protein C-protein C inhibitor complex in peripheral arterial disease.  Ann Vasc Surg. 2010;  24 (5) 588-595
  • 48 Schulman S, Eelde A, Blombäck M, Stenflo J. The plasma concentration of activated protein C appears normal in patients with haemophilia.  Haemophilia. 2009;  15 (2) 566-570
  • 49 Kölbel T, Strandberg K, Mattiasson I, Stenflo J, Lindblad B. Activated protein C-protein C inhibitor complex: a new biological marker for aortic aneurysms.  J Vasc Surg. 2006;  43 (5) 935-939
  • 50 Kölbel T, Donath T, Strandberg K et al.. Is increased thrombin activation in patients with abdominal aortic aneurysms dependent on area or volume of aneurysm thrombus mass?.  Angiology. 2010;  61 (1) 113-118
  • 51 Elf J L, Strandberg K, Svensson P J. The diagnostic performance of APC-PCI complex determination compared to D-dimer in the diagnosis of deep vein thrombosis.  J Thromb Thrombolysis. 2010;  29 (4) 465-470
  • 52 Uhrin P, Schöfer C, Zaujec J et al.. Male fertility and protein C inhibitor/plasminogen activator inhibitor-3 (PCI): localization of PCI in mouse testis and failure of single plasminogen activator knockout to restore spermatogenesis in PCI-deficient mice.  Fertil Steril. 2007;  88 (4, Suppl) 1049-1057
  • 53 España F, Navarro S, Medina P, Zorio E, Estellés A. The role of protein C inhibitor in human reproduction.  Semin Thromb Hemost. 2007;  33 (1) 41-45
  • 54 Suzuki K, Kise H, Nishioka J, Hayashi T. The interaction among protein C inhibitor, prostate-specific antigen, and the semenogelin system.  Semin Thromb Hemost. 2007;  33 (1) 46-52
  • 55 España F, Sánchez-Cuenca J, Fernández P J et al.. Inhibition of human sperm-zona-free hamster oocyte binding and penetration by protein C inhibitor.  Andrologia. 1999;  31 (4) 217-223
  • 56 Gianotten J, Schimmel A W, van der Veen F, Lombardi M P, Meijers J CM. Absence of mutations in the PCI gene in subfertile men.  Mol Hum Reprod. 2004;  10 (11) 807-813
  • 57 Bungum M, Giwercman A, Bungum L, Humaidan P, Rastkhani H, Giwercman Y L. Polymorphisms in the protein C inhibitor gene in in vitro fertilization failure.  Fertil Steril. 2010;  93 (1) 277-279
  • 58 Fujimoto H, Gabazza E C, Hataji O et al.. Thrombin-activatable fibrinolysis inhibitor and protein C inhibitor in interstitial lung disease.  Am J Respir Crit Care Med. 2003;  167 (12) 1687-1694
  • 59 Nishii Y, Gabazza E C, Fujimoto H et al.. Protective role of protein C inhibitor in monocrotaline-induced pulmonary hypertension.  J Thromb Haemost. 2006;  4 (11) 2331-2339
  • 60 Kan M, Zhang G H, Zarnegar R et al.. Hepatocyte growth factor/hepatopoietin A stimulates the growth of rat kidney proximal tubule epithelial cells (RPTE), rat nonparenchymal liver cells, human melanoma cells, mouse keratinocytes and stimulates anchorage-independent growth of SV-40 transformed RPTE.  Biochem Biophys Res Commun. 1991;  174 (1) 331-337
  • 61 Hamada T, Kamada H, Hayashi T et al.. Protein C inhibitor regulates hepatocyte growth factor activator-mediated liver regeneration in mice.  Gut. 2008;  57 (3) 365-373
  • 62 Han M H, Hwang S I, Roy D B et al.. Proteomic analysis of active multiple sclerosis lesions reveals therapeutic targets.  Nature. 2008;  451 (7182) 1076-1081
  • 63 Rosenzweig C N, Zhang Z, Sun X et al.. Predicting prostate cancer biochemical recurrence using a panel of serum proteomic biomarkers.  J Urol. 2009;  181 (3) 1407-1414
  • 64 Suzuki K, Hayashi T. Protein C and its inhibitor in malignancy.  Semin Thromb Hemost. 2007;  33 (7) 667-672
  • 65 Nishioka J, Ning M, Hayashi T, Suzuki K. Protein C inhibitor secreted from activated platelets efficiently inhibits activated protein C on phosphatidylethanolamine of platelet membrane and microvesicles.  J Biol Chem. 1998;  273 (18) 11281-11287
  • 66 Malleier J M, Oskolkova O, Bochkov V et al.. Regulation of protein C inhibitor (PCI) activity by specific oxidized and negatively charged phospholipids.  Blood. 2007;  109 (11) 4769-4776
  • 67 Baumgärtner P, Geiger M, Zieseniss S et al.. Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor.  J Cell Biol. 2007;  179 (4) 793-804
  • 68 Andersson E, Rydengård V, Sonesson A, Mörgelin M, Björck L, Schmidtchen A. Antimicrobial activities of heparin-binding peptides.  Eur J Biochem. 2004;  271 (6) 1219-1226
  • 69 Malmström E, Mörgelin M, Malmsten M et al.. Protein C inhibitor—a novel antimicrobial agent.  PLoS Pathog. 2009;  5 (12) e1000698

Joost C.M. MeijersPh.D. 

Experimental Vascular Medicine, G1-143, Academic Medical Center

Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands

Email: j.c.meijers@amc.uva.nl

    >