Three Decades of Research on Plasminogen Activator Inhibitor-1: A Multifaceted Serpin

Paul J. Declerck; Ann Gils

doi:10.1055/s-0033-1334487

Seminars in Thrombosis and Hemostasis, Table of Contents

Semin Thromb Hemost 2013; 39(04): 356-364
DOI: 10.1055/s-0033-1334487

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Three Decades of Research on Plasminogen Activator Inhibitor-1: A Multifaceted Serpin

Paul J. Declerck

¹Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium

,

Ann Gils

¹Department of Pharmaceutical and Pharmacological Sciences, Laboratory for Therapeutic and Diagnostic Antibodies, KU Leuven, Leuven, Belgium

› Author Affiliations

Abstract

Plasminogen activator inhibitor 1 (PAI-1) is the main inhibitor of tissue-type (t-PA) and urokinase-type (u-PA) plasminogen activator and therefore plays an important role in the plasminogen–plasmin system. PAI-1 is involved in a variety of cardiovascular diseases (mainly through inhibition of t-PA) as well as in cell migration and tumor development (mainly through inhibition of u-PA and interaction with vitronectin). PAI-1 is a unique member of the serpin superfamily, exhibiting particular unique conformational and functional properties. Because of its involvement in various biologic and pathophysiologic processes, PAI-1 has been the subject of many studies, including extensive structural investigations, in vitro cell biologic studies, in vivo animal studies, and epidemiologic studies. The review provides an overview on the current knowledge on PAI-1.

Keywords

plasminogen activator inhibitor 1 - PAI-1 - fibrinolysis - cancer - plasminogen activation - serpin

Full Text

References

References
1 Rijken DC, Lijnen HR. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost 2009; 7 (1) 4-13
2 Medcalf RL. Fibrinolysis, inflammation, and regulation of the plasminogen activating system. J Thromb Haemost 2007; 5 (Suppl. 01) 132-142
3 Duffy MJ, McGowan PM, Gallagher WM. Cancer invasion and metastasis: changing views. J Pathol 2008; 214 (3) 283-293
4 Loskutoff DJ, van Mourik JA, Erickson LA, Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci U S A 1983; 80 (10) 2956-2960
5 Simpson AJ, Booth NA, Moore NR, Bennett B. Distribution of plasminogen activator inhibitor (PAI-1) in tissues. J Clin Pathol 1991; 44 (2) 139-143
6 Andreasen PA, Georg B, Lund LR, Riccio A, Stacey SN. Plasminogen activator inhibitors: hormonally regulated serpins. Mol Cell Endocrinol 1990; 68 (1) 1-19
7 Irigoyen JP, Muñoz-Cánoves P, Montero L, Koziczak M, Nagamine Y. The plasminogen activator system: biology and regulation. Cell Mol Life Sci 1999; 56 (1–2) 104-132
8 Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost 2005; 3 (8) 1879-1883
9 Andreasen PA, Riccio A, Welinder KG , et al. Plasminogen activator inhibitor type-1: reactive center and amino-terminal heterogeneity determined by protein and cDNA sequencing. FEBS Lett 1986; 209 (2) 213-218
10 Ginsburg D, Zeheb R, Yang AY , et al. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest 1986; 78 (6) 1673-1680
11 Pannekoek H, Veerman H, Lambers H , et al. Endothelial plasminogen activator inhibitor (PAI): a new member of the Serpin gene family. EMBO J 1986; 5 (10) 2539-2544
12 Ny T, Sawdey M, Lawrence D, Millan JL, Loskutoff DJ. Cloning and sequence of a cDNA coding for the human beta-migrating endothelial-cell-type plasminogen activator inhibitor. Proc Natl Acad Sci U S A 1986; 83 (18) 6776-6780
13 Zeheb R, Gelehrter TD. Cloning and sequencing of cDNA for the rat plasminogen activator inhibitor-1. Gene 1988; 73 (2) 459-468
14 Mimuro J, Sawdey M, Hattori M, Loskutoff DJ. cDNA for bovine type 1 plasminogen activator inhibitor (PAI-1). Nucleic Acids Res 1989; 17 (21) 8872
15 Prendergast GC, Diamond LE, Dahl D, Cole MD. The c-myc-regulated gene mrl encodes plasminogen activator inhibitor 1. Mol Cell Biol 1990; 10 (3) 1265-1269
16 Hofmann KJ, Mayer EJ, Schultz LD, Socher SH, Reilly CF. Purification and characterization of recombinant rabbit plasminogen activator inhibitor-1 expressed in Saccharomyces cerevisae. Fibrinolysis 1992; 6: 263-272
17 Bijnens AP, Knockaert I, Cousin E, Kruithof EK, Declerck PJ. Expression and characterization of recombinant porcine plasminogen activator inhibitor-1. Thromb Haemost 1997; 77 (2) 350-356
18 Meissenheimer LM, Verbeke K, Declerck PJ, Gils A. Quantitation of vervet monkey (Chlorocebus aethiops) plasminogen activator inhibitor-1 in plasma and platelets. Thromb Haemost 2006; 95 (5) 902-903
19 Xue Y, Björquist P, Inghardt T , et al. Interfering with the inhibitory mechanism of serpins: crystal structure of a complex formed between cleaved plasminogen activator inhibitor type 1 and a reactive-centre loop peptide. Structure 1998; 6 (5) 627-636
20 Gils A, Pedersen KE, Skottrup P , et al. Biochemical importance of glycosylation of plasminogen activator inhibitor-1. Thromb Haemost 2003; 90 (2) 206-217
21 Lawrence D, Strandberg L, Grundström T, Ny T. Purification of active human plasminogen activator inhibitor 1 from Escherichia coli. Comparison with natural and recombinant forms purified from eucaryotic cells. Eur J Biochem 1989; 186 (3) 523-533
22 Van De Craen B, Scroyen I, Vranckx C , et al. Maximal PAI-1 inhibition in vivo requires neutralizing antibodies that recognize and inhibit glycosylated PAI-1. Thromb Res 2012; 129 (4) e126-e133
23 Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest 1984; 74 (4) 1465-1472
24 Chmielewska J, Rånby M, Wiman B. Evidence for a rapid inhibitor to tissue plasminogen activator in plasma. Thromb Res 1983; 31 (3) 427-436
25 Loskutoff DJ, Sawdey M, Mimuro J. Type 1 plasminogen activator inhibitor. Prog Hemost Thromb 1989; 9: 87-115
26 Booth NA, Simpson AJ, Croll A, Bennett B, MacGregor IR. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1988; 70 (3) 327-333
27 Declerck PJ, Alessi MC, Verstreken M, Kruithof EK, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor 1 in biologic fluids with a murine monoclonal antibody-based enzyme-linked immunosorbent assay. Blood 1988; 71 (1) 220-225
28 Kruithof EK, Nicolosa G, Bachmann F. Plasminogen activator inhibitor 1: development of a radioimmunoassay and observations on its plasma concentration during venous occlusion and after platelet aggregation. Blood 1987; 70 (5) 1645-1653
29 Owensby DA, Morton PA, Wun TC, Schwartz AL. Binding of plasminogen activator inhibitor type-1 to extracellular matrix of Hep G2 cells. Evidence that the binding protein is vitronectin. J Biol Chem 1991; 266 (7) 4334-4340
30 Seiffert D, Mimuro J, Schleef RR, Loskutoff DJ. Interactions between type 1 plasminogen activator inhibitor, extracellular matrix and vitronectin. Cell Differ Dev 1990; 32 (3) 287-292
31 Declerck PJ, De Mol M, Alessi MC , et al. Purification and characterization of a plasminogen activator inhibitor 1 binding protein from human plasma. Identification as a multimeric form of S protein (vitronectin). J Biol Chem 1988; 263 (30) 15454-15461
32 Hekman CM, Loskutoff DJ. Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem 1985; 260 (21) 11581-11587
33 Vaughan DE, Declerck PJ, Van Houtte E, De Mol M, Collen D. Studies of recombinant plasminogen activator inhibitor-1 in rabbits. Pharmacokinetics and evidence for reactivation of latent plasminogen activator inhibitor-1 in vivo. Circ Res 1990; 67 (5) 1281-1286
34 Declerck PJ, De Mol M, Vaughan DE, Collen D. Identification of a conformationally distinct form of plasminogen activator inhibitor-1, acting as a noninhibitory substrate for tissue-type plasminogen activator. J Biol Chem 1992; 267 (17) 11693-11696
35 Urano T, Strandberg L, Johansson LBA, Ny T. A substrate-like form of plasminogen-activator-inhibitor type 1. Conversions between different forms by sodium dodecyl sulphate. Eur J Biochem 1992; 209 (3) 985-992
36 Munch M, Heegaard CW, Andreasen PA. Interconversions between active, inert and substrate forms of denatured/refolded type-1 plasminogen activator inhibitor. Biochim Biophys Acta 1993; 1202 (1) 29-37
37 De Taeye B, Gils A, Declerck PJ. The story of the serpin plasminogen activator inhibitor 1: is there any need for another mutant?. Thromb Haemost 2004; 92 (5) 898-924
38 Mottonen J, Strand A, Symersky J , et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature 1992; 355 (6357) 270-273
39 Aertgeerts K, De Bondt HL, De Ranter CJ, Declerck PJ. Mechanisms contributing to the conformational and functional flexibility of plasminogen activator inhibitor-1. Nat Struct Biol 1995; 2 (10) 891-897
40 Nar H, Bauer M, Stassen JM, Lang D, Gils A, Declerck PJ. Plasminogen activator inhibitor 1. Structure of the native serpin, comparison to its other conformers and implications for serpin inactivation. J Mol Biol 2000; 297 (3) 683-695
41 Sharp AM, Stein PE, Pannu NS , et al. The active conformation of plasminogen activator inhibitor 1, a target for drugs to control fibrinolysis and cell adhesion. Structure 1999; 7 (2) 111-118
42 Jensen JK, Thompson LC, Bucci JC , et al. Crystal structure of plasminogen activator inhibitor-1 in an active conformation with normal thermodynamic stability. J Biol Chem 2011; 286 (34) 29709-29717
43 Lin Z, Jiang L, Yuan C , et al. Structural basis for recognition of urokinase-type plasminogen activator by plasminogen activator inhibitor-1. J Biol Chem 2011; 286 (9) 7027-7032
44 Lindahl TL, Sigurdardottir O, Wiman B. Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb Haemost 1989; 62 (2) 748-751
45 Sancho E, Tonge DW, Hockney RC, Booth NA. Purification and characterization of active and stable recombinant plasminogen-activator inhibitor accumulated at high levels in Escherichia coli. Eur J Biochem 1994; 224 (1) 125-134
46 Boncela J, Papiewska I, Fijalkowska I, Walkowiak B, Cierniewski CS. Acute phase protein alpha 1-acid glycoprotein interacts with plasminogen activator inhibitor type 1 and stabilizes its inhibitory activity. J Biol Chem 2001; 276 (38) 35305-35311
47 Berkenpas MB, Lawrence DA, Ginsburg D. Molecular evolution of plasminogen activator inhibitor-1 functional stability. EMBO J 1995; 14 (13) 2969-2977
48 Vleugels N, Gils A, Mannaerts S, Knockaert I, Declerck PJ. Evaluation of the mechanism of inactivation of plasminogen activator inhibitor-1 by monoclonal antibodies using a stable variant. Fibrinolysis & Proteolysis. 1998; 12: 277-282
49 Dewilde M, Strelkov SV, Rabijns A, Declerck PJ. High quality structure of cleaved PAI-1-stab. J Struct Biol 2009; 165 (2) 126-132
50 Stoop AA, Eldering E, Dafforn TR, Read RJ, Pannekoek H. Different structural requirements for plasminogen activator inhibitor 1 (PAI-1) during latency transition and proteinase inhibition as evidenced by phage-displayed hypermutated PAI-1 libraries. J Mol Biol 2001; 305 (4) 773-783
51 Chorostowska-Wynimko J, Swiercz R, Skrzypczak-Jankun E, Wojtowicz A, Selman SH, Jankun J. A novel form of the plasminogen activator inhibitor created by cysteine mutations extends its half-life: relevance to cancer and angiogenesis. Mol Cancer Ther 2003; 2 (1) 19-28
52 Ehrlich HJ, Gebbink RK, Keijer J, Linders M, Preissner KT, Pannekoek H. Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. J Biol Chem 1990; 265 (22) 13029-13035
53 Keijer J, Linders M, Wegman JJ, Ehrlich HJ, Mertens K, Pannekoek H. On the target specificity of plasminogen activator inhibitor 1: the role of heparin, vitronectin, and the reactive site. Blood 1991; 78 (5) 1254-1261
54 Rezaie AR. Vitronectin functions as a cofactor for rapid inhibition of activated protein C by plasminogen activator inhibitor-1. Implications for the mechanism of profibrinolytic action of activated protein C. J Biol Chem 2001; 276 (19) 15567-15570
55 Carrell R, Travis J. Alpha-1-antitrypsin and the serpins - variation and countervariation. Trends Biochem Sci 1985; 10: 20-24
56 Sherman PM, Lawrence DA, Yang AY , et al. Saturation mutagenesis of the plasminogen activator inhibitor-1 reactive center. J Biol Chem 1992; 267 (11) 7588-7595
57 Sherman PM, Lawrence DA, Verhamme IM, Paielli D, Shore JD, Ginsburg D. Identification of tissue-type plasminogen activator-specific plasminogen activator inhibitor-1 mutants. Evidence that second sites of interaction contribute to target specificity. J Biol Chem 1995; 270 (16) 9301-9306
58 Gramling MW, Church FC. Plasminogen activator inhibitor-1 is an aggregate response factor with pleiotropic effects on cell signaling in vascular disease and the tumor microenvironment. Thromb Res 2010; 125 (5) 377-381
59 De Taeye B, Smith LH, Vaughan DE. Plasminogen activator inhibitor-1: a common denominator in obesity, diabetes and cardiovascular disease. Curr Opin Pharmacol 2005; 5 (2) 149-154
60 Declerck PJ, Juhan-Vague I, Felez J, Wiman B. Pathophysiology of fibrinolysis. J Intern Med 1994; 236 (4) 425-432
61 Juhan-Vague I, Alessi MC, Declerck PJ. Pathophysiology of fibrinolysis. Baillieres Clin Haematol 1995; 8 (2) 329-343
62 Hamsten A, Wiman B, de Faire U, Blombäck M. Increased plasma levels of a rapid inhibitor of tissue plasminogen activator in young survivors of myocardial infarction. N Engl J Med 1985; 313 (25) 1557-1563
63 Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342 (8879) 1076-1079
64 Nilsson IM, Ljungnér H, Tengborn L. Two different mechanisms in patients with venous thrombosis and defective fibrinolysis: low concentration of plasminogen activator or increased concentration of plasminogen activator inhibitor. Br Med J (Clin Res Ed) 1985; 290 (6480) 1453-1456
65 Wiman B, Ljungberg B, Chmielewska J, Urdén G, Blombäck M, Johnsson H. The role of the fibrinolytic system in deep vein thrombosis. J Lab Clin Med 1985; 105 (2) 265-270
66 Schulman S, Wiman B. Duration of Anticoagulation (DURAC) Trial Study Group. The significance of hypofibrinolysis for the risk of recurrence of venous thromboembolism. Thromb Haemost 1996; 75 (4) 607-611
67 Siemens HJ, Brueckner S, Hagelberg S, Wagner T, Schmucker P. Course of molecular hemostatic markers during and after different surgical procedures. J Clin Anesth 1999; 11 (8) 622-629
68 Binder BR, Mihaly J, Prager GW. uPAR-uPA-PAI-1 interactions and signaling: a vascular biologist's view. Thromb Haemost 2007; 97 (3) 336-342
69 Sandford RM, Bown MJ, London NJ, Sayers RD. The genetic basis of abdominal aortic aneurysms: a review. Eur J Vasc Endovasc Surg 2007; 33 (4) 381-390
70 Mesters RM, Flörke N, Ostermann H, Kienast J. Increase of plasminogen activator inhibitor levels predicts outcome of leukocytopenic patients with sepsis. Thromb Haemost 1996; 75 (6) 902-907
71 Kornelisse RF, Hazelzet JA, Savelkoul HF , et al. The relationship between plasminogen activator inhibitor-1 and proinflammatory and counterinflammatory mediators in children with meningococcal septic shock. J Infect Dis 1996; 173 (5) 1148-1156
72 Arnman V, Nilsson A, Stemme S, Risberg B, Rymo L. Expression of plasminogen activator inhibitor-1 mRNA in healthy, atherosclerotic and thrombotic human arteries and veins. Thromb Res 1994; 76 (5) 487-499
73 Fay WP, Garg N, Sunkar M. Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol 2007; 27 (6) 1231-1237
74 Narayanaswamy M, Wright KC, Kandarpa K. Animal models for atherosclerosis, restenosis, and endovascular graft research. J Vasc Interv Radiol 2000; 11 (1) 5-17
75 Schneiderman J, Sawdey MS, Keeton MR , et al. Increased type 1 plasminogen activator inhibitor gene expression in atherosclerotic human arteries. Proc Natl Acad Sci U S A 1992; 89 (15) 6998-7002
76 Robbie LA, Booth NA, Brown AJ, Bennett B. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16 (4) 539-545
77 Lupu F, Bergonzelli GE, Heim DA , et al. Localization and production of plasminogen activator inhibitor-1 in human healthy and atherosclerotic arteries. Arterioscler Thromb 1993; 13 (7) 1090-1100
78 Prins MH, Hirsh J. A critical review of the evidence supporting a relationship between impaired fibrinolytic activity and venous thromboembolism. Arch Intern Med 1991; 151 (9) 1721-1731
79 Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson SG. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. ECAT Study Group. European Concerted Action on Thrombosis and Disabilities. Circulation 1996; 94 (9) 2057-2063
80 Thögersen AM, Jansson JH, Boman K , et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation 1998; 98 (21) 2241-2247
81 Folsom AR, Aleksic N, Park E, Salomaa V, Juneja H, Wu KK. Prospective study of fibrinolytic factors and incident coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) Study. Arterioscler Thromb Vasc Biol 2001; 21 (4) 611-617
82 Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46 (5) 860-867
83 Nordt TK, Sawa H, Fujii S, Bode C, Sobel BE. Augmentation of arterial endothelial cell expression of the plasminogen activator inhibitor type-1 (PAI-1) gene by proinsulin and insulin in vivo. J Mol Cell Cardiol 1998; 30 (8) 1535-1543
84 Schafer K, Müller K, Hecke A , et al. Enhanced thrombosis in atherosclerosis-prone mice is associated with increased arterial expression of plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23 (11) 2097-2103
85 Dawson SJ, Wiman B, Hamsten A, Green F, Humphries S, Henney AM. The two allele sequences of a common polymorphism in the promoter of the plasminogen activator inhibitor-1 (PAI-1) gene respond differently to interleukin-1 in HepG2 cells. J Biol Chem 1993; 268 (15) 10739-10745
86 Ringelstein M, Jung A, Berger K , et al. Promotor polymorphisms of plasminogen activator inhibitor-1 and other thrombophilic genotypes in cerebral venous thrombosis: a case-control study in adults. J Neurol 2012; 259 (11) 2287-2292
87 Tsantes AE, Nikolopoulos GK, Bagos PG, Bonovas S, Kopterides P, Vaiopoulos G. The effect of the plasminogen activator inhibitor-1 4G/5G polymorphism on the thrombotic risk. Thromb Res 2008; 122 (6) 736-742
88 Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med 2002; 126 (11) 1401-1404
89 Schleef RR, Higgins DL, Pillemer E, Levitt LJ. Bleeding diathesis due to decreased functional activity of type 1 plasminogen activator inhibitor. J Clin Invest 1989; 83 (5) 1747-1752
90 Mehta R, Shapiro AD. Plasminogen activator inhibitor type 1 deficiency. Haemophilia 2008; 14 (6) 1255-1260
91 Fay WP, Parker AC, Condrey LR, Shapiro AD. Human plasminogen activator inhibitor-1 (PAI-1) deficiency: characterization of a large kindred with a null mutation in the PAI-1 gene. Blood 1997; 90 (1) 204-208
92 Zhang ZY, Wang ZY, Dong NZ, Bai X, Zhang W, Ruan CG. A case of deficiency of plasma plasminogen activator inhibitor-1 related to Ala15Thr mutation in its signal peptide. Blood Coagul Fibrinolysis 2005; 16 (1) 79-84
93 Jänicke F, Schmitt M, Pache L , et al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat 1993; 24 (3) 195-208
94 Knoop A, Andreasen PA, Andersen JA , et al. Prognostic significance of urokinase-type plasminogen activator and plasminogen activator inhibitor-1 in primary breast cancer. Br J Cancer 1998; 77 (6) 932-940
95 Nekarda H, Siewert JR, Schmitt M, Ulm K. Tumour-associated proteolytic factors uPA and PAI-1 and survival in totally resected gastric cancer. Lancet 1994; 343 (8889) 117
96 Konecny G, Untch M, Pihan A , et al. Association of urokinase-type plasminogen activator and its inhibitor with disease progression and prognosis in ovarian cancer. Clin Cancer Res 2001; 7 (6) 1743-1749
97 Kuhn W, Schmalfeldt B, Reuning U , et al. Prognostic significance of urokinase (uPA) and its inhibitor PAI-1 for survival in advanced ovarian carcinoma stage FIGO IIIc. Br J Cancer 1999; 79 (11-12) 1746-1751
98 Komiyama S, Aoki D, Saitoh E, Komiyama M, Udagawa Y. Biological significance of plasminogen activator inhibitor-1 expression in ovarian clear cell adenocarcinoma. Eur J Gynaecol Oncol 2011; 32 (6) 611-614
99 Becker M, Szarvas T, Wittschier M , et al. Prognostic impact of plasminogen activator inhibitor type 1 expression in bladder cancer. Cancer 2010; 116 (19) 4502-4512
100 Gao S, Nielsen BS, Krogdahl A , et al. Epigenetic alterations of the SERPINE1 gene in oral squamous cell carcinomas and normal oral mucosa. Genes Chromosomes Cancer 2010; 49 (6) 526-538
101 Halamkova J, Kiss I, Pavlovsky Z , et al. Clinical relevance of uPA, uPAR, PAI 1 and PAI 2 tissue expression and plasma PAI 1 level in colorectal carcinoma patients. Hepatogastroenterology 2011; 58 (112) 1918-1925
102 Durand MK, Bødker JS, Christensen A , et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost 2004; 91 (3) 438-449
103 McMahon B, Kwaan HC. The plasminogen activator system and cancer. Pathophysiol Haemost Thromb 2008; 36 (3-4) 184-194
104 Binder BR, Mihaly J. The plasminogen activator inhibitor “paradox” in cancer. Immunol Lett 2008; 118 (2) 116-124
105 Kwaan HC, Wang J, Svoboda K, Declerck PJ. Plasminogen activator inhibitor 1 may promote tumour growth through inhibition of apoptosis. Br J Cancer 2000; 82 (10) 1702-1708
106 Schneider DJ, Chen Y, Sobel BE. The effect of plasminogen activator inhibitor type 1 on apoptosis. Thromb Haemost 2008; 100 (6) 1037-1040
107 Gutierrez LS, Schulman A, Brito-Robinson T, Noria F, Ploplis VA, Castellino FJ. Tumor development is retarded in mice lacking the gene for urokinase-type plasminogen activator or its inhibitor, plasminogen activator inhibitor-1. Cancer Res 2000; 60 (20) 5839-5847
108 Brodsky S, Chen J, Lee A, Akassoglou K, Norman J, Goligorsky MS. Plasmin-dependent and -independent effects of plasminogen activators and inhibitor-1 on ex vivo angiogenesis. Am J Physiol Heart Circ Physiol 2001; 281 (4) H1784-H1792
109 Stefansson S, Petitclerc E, Wong MK, McMahon GA, Brooks PC, Lawrence DA. Inhibition of angiogenesis in vivo by plasminogen activator inhibitor-1. J Biol Chem 2001; 276 (11) 8135-8141
110 Czekay R-P, Loskutoff DJ. Unexpected role of plasminogen activator inhibitor 1 in cell adhesion and detachment. Exp Biol Med (Maywood) 2004; 229 (11) 1090-1096
111 Kwaan HC, Mazar AP, McMahon BJ. The apparent uPA/PAI-1 paradox in cancer: more than meets the eye. Semin Thromb Hemost 2013; 39 (4) 382-391
112 Lijnen HR. Pleiotropic functions of plasminogen activator inhibitor-1. J Thromb Haemost 2005; 3 (1) 35-45
113 Cesari M, Pahor M, Incalzi RA. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther 2010; 28 (5) e72-e91
114 Lijnen HR, Juhan-Vague I. The fibrinolytic system and obesity. Thromb Haemost 2002; 88 (5) 882
115 Morange PE, Lijnen HR, Alessi MC, Kopp F, Collen D, Juhan-Vague I. Influence of PAI-1 on adipose tissue growth and metabolic parameters in a murine model of diet-induced obesity. Arterioscler Thromb Vasc Biol 2000; 20 (4) 1150-1154
116 Lijnen HR, Maquoi E, Morange P , et al. Nutritionally induced obesity is attenuated in transgenic mice overexpressing plasminogen activator inhibitor-1. Arterioscler Thromb Vasc Biol 2003; 23 (1) 78-84
117 Lijnen HR. Effect of plasminogen activator inhibitor-1 deficiency on nutritionally-induced obesity in mice. Thromb Haemost 2005; 93 (5) 816-819
118 Schäfer K, Fujisawa K, Konstantinides S, Loskutoff DJ. Disruption of the plasminogen activator inhibitor 1 gene reduces the adiposity and improves the metabolic profile of genetically obese and diabetic ob/ob mice. FASEB J 2001; 15 (10) 1840-1842
119 Alessi MC, Juhan-Vague I. PAI-1 and the metabolic syndrome: links, causes, and consequences. Arterioscler Thromb Vasc Biol 2006; 26 (10) 2200-2207
120 Dellas C, Loskutoff DJ. Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease. Thromb Haemost 2005; 93 (4) 631-640
121 Alessi MC, Nicaud V, Scroyen I , et al; DESIR Study Group. Association of vitronectin and plasminogen activator inhibitor-1 levels with the risk of metabolic syndrome and type 2 diabetes mellitus. Results from the D.E.S.I.R. prospective cohort. Thromb Haemost 2011; 106 (3) 416-422
122 Declerck PJ, Gils A, De Taeye B. Use of mouse models to study plasminogen activator inhibitor-1. Methods Enzymol 2011; 499: 77-104
123 Dewilde M, Van De Craen B, Compernolle G , et al. Subtle structural differences between human and mouse PAI-1 reveal the basis for biochemical differences. J Struct Biol 2010; 171 (1) 95-101
124 Gils A, Meissenheimer LM, Compernolle G, Declerck PJ. Species-dependent molecular drug targets in plasminogen activator inhibitor-1 (PAI-1). Thromb Haemost 2009; 102 (3) 609-610
125 Matsuo O, Lijnen HR, Ueshima S, Kojima S, Smyth SS. A guide to murine fibrinolytic factor structure, function, assays, and genetic alterations. J Thromb Haemost 2007; 5 (4) 680-689
126 Lijnen HR, van Hoef B, Beelen V, Collen D. Characterization of the murine plasma fibrinolytic system. Eur J Biochem 1994; 224 (3) 863-871
127 Kawasaki T, Dewerchin M, Lijnen HR, Vermylen J, Hoylaerts MF. Vascular release of plasminogen activator inhibitor-1 impairs fibrinolysis during acute arterial thrombosis in mice. Blood 2000; 96 (1) 153-160
128 Van De Craen B, Scroyen I, Abdelnabi R , et al. Characterization of a panel of monoclonal antibodies toward mouse PAI-1 that exert a significant profibrinolytic effect in vivo. Thromb Res 2011; 128 (1) 68-76
129 Leik CE, Su EJ, Nambi P, Crandall DL, Lawrence DA. Effect of pharmacologic plasminogen activator inhibitor-1 inhibition on cell motility and tumor angiogenesis. J Thromb Haemost 2006; 4 (12) 2710-2715
130 Carmeliet P, Stassen JM, Schoonjans L , et al. Plasminogen activator inhibitor-1 gene-deficient mice. II. Effects on hemostasis, thrombosis, and thrombolysis. J Clin Invest 1993; 92 (6) 2756-2760
131 Smith LH, Dixon JD, Stringham JR , et al. Pivotal role of PAI-1 in a murine model of hepatic vein thrombosis. Blood 2006; 107 (1) 132-134
132 Farrehi PM, Ozaki CK, Carmeliet P, Fay WP. Regulation of arterial thrombolysis by plasminogen activator inhibitor-1 in mice. Circulation 1998; 97 (10) 1002-1008
133 Fay WP, Parker AC, Ansari MN, Zheng X, Ginsburg D. Vitronectin inhibits the thrombotic response to arterial injury in mice. Blood 1999; 93 (6) 1825-1830
134 Zhu Y, Carmeliet P, Fay WP. Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance. Circulation 1999; 99 (23) 3050-3055
135 Boulaftali Y, Lamrani L, Rouzaud MC , et al. The mouse dorsal skinfold chamber as a model for the study of thrombolysis by intravital microscopy. Thromb Haemost 2012; 107 (5) 962-971
136 Eitzman DT, Westrick RJ, Nabel EG, Ginsburg D. Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 2000; 95 (2) 577-580
137 Matsuno H, Kozawa O, Niwa M , et al. Differential role of components of the fibrinolytic system in the formation and removal of thrombus induced by endothelial injury. Thromb Haemost 1999; 81 (4) 601-604
138 Abderrahmani R, François A, Buard V , et al. PAI-1-dependent endothelial cell death determines severity of radiation-induced intestinal injury. PLoS ONE 2012; 7 (4) e35740
139 Eren M, Painter CA, Atkinson JB, Declerck PJ, Vaughan DE. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation 2002; 106 (4) 491-496
140 Eren M, Gleaves LA, Atkinson JB, King LE, Declerck PJ, Vaughan DE. Reactive site-dependent phenotypic alterations in plasminogen activator inhibitor-1 transgenic mice. J Thromb Haemost 2007; 5 (7) 1500-1508
141 Erickson LA, Fici GJ, Lund JE, Boyle TP, Polites HG, Marotti KR. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 1990; 346 (6279) 74-76
142 Eitzman DT, McCoy RD, Zheng X , et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996; 97 (1) 232-237
143 Narasaki R, Xu Z, Liang Z, Fung LC, Donahue D, Castellino FJ, Ploplis VA. The vitronectin-binding domain of plasminogen activator inhibitor-1 plays an important functional role in lipopolysaccharide-induced lethality in mice. J Thromb Haemost 2012; 10: 2618-2621
144 Nagai N, De Mol M, Lijnen HR, Carmeliet P, Collen D. Role of plasminogen system components in focal cerebral ischemic infarction: a gene targeting and gene transfer study in mice. Circulation 1999; 99 (18) 2440-2444
145 Nagai N, Suzuki Y, Van Hoef B, Lijnen HR, Collen D. Effects of plasminogen activator inhibitor-1 on ischemic brain injury in permanent and thrombotic middle cerebral artery occlusion models in mice. J Thromb Haemost 2005; 3 (7) 1379-1384
146 Nagai N, Van Hoef B, Lijnen HR. Plasminogen activator inhibitor-1 contributes to the deleterious effect of obesity on the outcome of thrombotic ischemic stroke in mice. J Thromb Haemost 2007; 5 (8) 1726-1731
147 Andreasen PA. PAI-1—a potential therapeutic target in cancer. Curr Drug Targets 2007; 8 (9) 1030-1041
148 Soff GA, Sanderowitz J, Gately S , et al. Expression of plasminogen activator inhibitor type 1 by human prostate carcinoma cells inhibits primary tumor growth, tumor-associated angiogenesis, and metastasis to lung and liver in an athymic mouse model. J Clin Invest 1995; 96 (6) 2593-2600
149 Devy L, Blacher S, Grignet-Debrus C , et al. The pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent. FASEB J 2002; 16 (2) 147-154
150 Lambert V, Munaut C, Carmeliet P , et al. Dose-dependent modulation of choroidal neovascularization by plasminogen activator inhibitor type I: implications for clinical trials. Invest Ophthalmol Vis Sci 2003; 44 (6) 2791-2797
151 McMahon GA, Petitclerc E, Stefansson S , et al. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem 2001; 276 (36) 33964-33968
152 Gils A, Declerck PJ. The structural basis for the pathophysiological relevance of PAI-I in cardiovascular diseases and the development of potential PAI-I inhibitors. Thromb Haemost 2004; 91 (3) 425-437
153 Van De Craen B, Declerck PJ, Gils A. The biochemistry, physiology and pathological roles of PAI-1 and the requirements for PAI-1 inhibition in vivo. Thromb Res 2012; 130 (4) 576-585
154 Lee SH, Eren M, Vaughan DE, Schleimer RP, Cho SH. A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma. Am J Respir Cell Mol Biol 2012; 46 (6) 842-846
155 Watanabe R, Nakajima T, Ogawa M , et al. Effects of pharmacological suppression of plasminogen activator inhibitor-1 in myocardial remodeling after ischemia reperfusion injury. Int Heart J 2011; 52 (6) 388-392
156 Tashiro Y, Nishida C, Sato-Kusubata K , et al. Inhibition of PAI-1 induces neutrophil-driven neoangiogenesis and promotes tissue regeneration via production of angiocrine factors in mice. Blood 2012; 119 (26) 6382-6393