Protein C Inhibitor

Joost C.M. Meijers; Heiko Herwald

doi:10.1055/s-0031-1276583

Seminars in Thrombosis and Hemostasis, Table of Contents

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

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

Abstract

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.

KEYWORDS

Protein C inhibitor - SERPIN - inhibition

Full Text

References

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