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Thromb Haemost 2005; 93(04): 631-640
DOI: 10.1160/TH05-01-0033
Theme Issue Article
Schattauer GmbH

Historical analysis of PAI-1 from its discovery to its potential role in cell motility and disease

Claudia Dellas
1   The Scripps Research Institute, Department of Cell Biology, Division of Vascular Biology, La Jolla, California, USA
,
David J. Loskutoff
1   The Scripps Research Institute, Department of Cell Biology, Division of Vascular Biology, La Jolla, California, USA
› Author Affiliations
Further Information

Publication History

Received 17 January 2005

Accepted after revision 26 January 2005

Publication Date:
14 December 2017 (online)

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Summary

Although plasminogen activator inhibitor 1 (PAI-1) is one of the primary regulators of the fibrinolytic system, it also has dramatic effects on cell adhesion, detachment and migration. PAI-1 also differs from other serine protease inhibitors (serpins) in that it is a trace protein in plasma, it has a short half-life in vivo, its synthesis is highly regulated, and it binds to the adhesive glycoprotein vitronectin (VN) with high affinity and specificity. These unique and diverse properties of PAI-1 probably account for the many observations in the literature that correlate abnormalities in PAI-1 gene expression with a variety of pathological conditions. In this review, we discuss the discovery, origin, properties and regulation of PAI-1, and then speculate about its potential role in vascular disease, fibrosis, obesity and the metabolic syndrome, and cancer.

Keywords

PAI-1 - vascular disease - fibrosis - obesity - cancer
 

  • References

  • 1 Reich E. Activation of plasminogen: A general mechanism for producing localized extracellular proteolysis. In: Berlin RD, Herrmann H, Lepou IH, Tanzer JM, editors. Molecular Basis of Biological Degradative Proteases. New York: Academic Press; 1978: 155-69.
    Google Scholar
  • 2 Vassalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 3 Andreasen PA, Egelung R, Petersen HH. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
    CrossrefPubMedGoogle Scholar
  • 4 Collen D, Lijnen HR. Tissue-type plasminogen activator: a historical perspective and personal account. J Thromb Haemost 2004; 2: 541-6.
    CrossrefPubMedGoogle Scholar
  • 5 Stiko A, Hervio L, Loskutoff DJ. Plasminogen activator inhibitors. In: Colman RW, Hirsch J, Marder VJ, Clowes AW, George JN, editors.. Hemostasis and Thrombosis: Basic principles & clinical practice.. Philadelphia, PA: Lippincott William & Wilkins; 2000: 355-65
    Google Scholar
  • 6 Sprengers ED, Kluft C. Plasminogen activator inhibitors. Blood 1987; 69: 381-7.
    CrossrefPubMedGoogle Scholar
  • 7 Loskutoff DJ, Sawdey M, Mimuro J. Type 1 plasminogen activator inhibitor. In: Coller B, editor. Progress in Hemostasis and Thrombosis. Philadelphia: W.B.Saunders Company; 1988: 87-115.
    Google Scholar
  • 8 Kruithof EK, Baker MS, Bunn CL. Biological and clinical aspects of plasminogen activator inhibitor type 2. Blood 1995; 86: 4007-24.
    CrossrefPubMedGoogle Scholar
  • 9 van Mourik JA, Lawrence DA, Loskutoff DJ. Purification of an inhibitor of plasminogen activator (antiactivator) synthesized by endothelial cells. J Biol Chem 1984; 259: 14914-21.
    CrossrefPubMedGoogle Scholar
  • 10 Ny T, Sawdey M, Lawrence D. et al. 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: 6776-80.
    CrossrefPubMedGoogle Scholar
  • 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: 2539-44.
    CrossrefPubMedGoogle Scholar
  • 12 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: 213-8.
    CrossrefPubMedGoogle Scholar
  • 13 Ginsburg D, Zeheb R, Yang AY. et al. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest 1986; 78: 1673-80.
    CrossrefPubMedGoogle Scholar
  • 14 Yepes M, Lawrence DA. Neuroserpin: a selective inhibitor of tissue-type plasminogen activator in the central nervous system. Thromb Haemost 2004; 91: 457-64.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Simpson AJ, Booth NA, Moore NR. et al. Distribution of plasminogen activator inhibitor (PAI-1) in tissues. J Clin Pathol 1991; 44: 139-43.
    CrossrefPubMedGoogle Scholar
  • 16 Lucore CL, Fujii S, Wun TC. et al. Regulation of the expression of type 1 plasminogen activator inhibitor in Hep G2 cells by epidermal growth factor. J Biol Chem 1988; 263: 15845-8.
    CrossrefPubMedGoogle Scholar
  • 17 Kruithof EK, Gudinchet A, Bachmann F. Plasminogen activator inhibitor 1 and plasminogen activator inhibitor 2 in various disease states. Thromb Haemost 1988; 59: 7-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo. Tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest 1991; 88: 1346-53.
    CrossrefPubMedGoogle Scholar
  • 19 Quax PHA, van den Hoogen CM, Verheijen JH. et al. Endotoxin induction of plasminogen activator and plasminogen activator inhibitor type 1 mRNA in rat tissues in vivo. J Biol Chem 1990; 265: 15560-3.
    CrossrefPubMedGoogle Scholar
  • 20 Loskutoff DJ, Samad F. The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol 1998; 18: 1-6.
    CrossrefPubMedGoogle Scholar
  • 21 Erickson LA, Hekman CM, Loskutoff DJ. The primary plasminogen-activator inhibitors in endothelial cells, platelets, serum, and plasma are immunologically related. Proc Natl Acad Sci U S A 1985; 82: 8710-4.
    CrossrefPubMedGoogle Scholar
  • 22 Booth NA, Simpson AJ, Croll A. et al. Plasminogen activator inhibitor (PAI-1) in plasma and platelets. Br J Haematol 1988; 70: 327-33.
    CrossrefPubMedGoogle Scholar
  • 23 Fay WP, Eitzman DT, Shapiro AD. et al. Platelets inhibit fibrinolysis in vitro by both plasminogen activator inhibitor-1-dependent and -independent mechanisms. Blood 1994; 83: 351-6.
    CrossrefPubMedGoogle Scholar
  • 24 Fearns C, Samad F, Loskutoff DJ. Synthesis and localization of PAI-1 in the vessel wall. In: Vadas M, Harlan J, editors. Vascular Control of Hemostasis. Advances in Vacular Biology. Camberwell, Victoria, Australia: Gordon and Breach Publishers; 1996: 207-26.
    Google Scholar
  • 25 Samad F, Yamamoto K, Loskutoff DJ. Distribution and regulation of plasminogen activator inhibitor-1 in murine adipose tissue in vivo. Induction by tumor necrosis factor-alpha and lipopolysaccharide. J Clin Invest 1996; 97: 37-46.
    CrossrefPubMedGoogle Scholar
  • 26 Fearns C, Loskutoff DJ. Induction of plasminogen activator inhibitor 1 gene expression in murine liver by lipopolysaccharide. Cellular localization and role of endogenous tumor necrosis factor-alpha. Am J Pathol 1997; 150: 579-90.
    PubMedGoogle Scholar
  • 27 Stefansson S, McMahon GA, Petitclerc E. et al. Plasminogen activator inhibitor-1 in tumor growth, angiogenesis and vascular remodeling. Curr Pharm Des 2003; 9: 1545-64.
    CrossrefPubMedGoogle Scholar
  • 28 Hekman CM, Loskutoff DJ. Endothelial cells produce a latent inhibitor of plasminogen activators that can be activated by denaturants. J Biol Chem 1985; 260: 11581-7.
    CrossrefPubMedGoogle Scholar
  • 29 Levin EG, Santell L. Conversion of the active to latent plasminogen activator inhibitor from human endothelial cells. Blood 1987; 70: 1090-8.
    CrossrefPubMedGoogle Scholar
  • 30 Mottonen J, Strand A, Symersky J. et al. Structural basis of latency in plasminogen activator inhibitor-1. Nature 1992; 355: 270-3.
    CrossrefPubMedGoogle Scholar
  • 31 Hekman CM, Loskutoff DJ. Bovine plasminogen activator inhibitor 1: specificity determinations and comparison of the active, latent, and guanidine-activated forms. Biochemistry 1988; 27: 2911-8.
    CrossrefPubMedGoogle Scholar
  • 32 Lindahl TL, Sigurdardottir O, Wiman B. Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb Haemost 1989; 62: 748-51.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Lambers JW, Cammenga M, Konig BW. et al. Activation of human endothelial cell-type plasminogen activator inhibitor (PAI-1) by negatively charged phospholipids. J Biol Chem 1987; 262: 17492-6.
    CrossrefPubMedGoogle Scholar
  • 34 Stringer HA, van Swieten P, Heijnen HF. et al. Plasminogen activator inhibitor-1 released from activated platelets plays a key role in thrombolysis resistance. Studies with thrombi generated in the Chandler loop. Arterioscler Thromb 1994; 14: 1452-8.
    CrossrefPubMedGoogle Scholar
  • 35 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: 15454-61.
    CrossrefPubMedGoogle Scholar
  • 36 Wiman B, Almquist A, Sigurdardottir O. et al. Plasminogen activator inhibitor 1 (PAI) is bound to vitronectin in plasma. FEBS Lett 1988; 242: 125-8.
    CrossrefPubMedGoogle Scholar
  • 37 Ehrlich HJ, Gebbink RK, Keijer J. et al. Alteration of serpin specificity by a protein cofactor. Vitronectin endows plasminogen activator inhibitor 1 with thrombin inhibitory properties. J Biol Chem 1990; 265: 13029-135.
    CrossrefPubMedGoogle Scholar
  • 38 Seiffert D, Ciambrone G, Wagner NV. et al. The somatomedin B domain of vitronectin. Structural requirements for the binding and stabilization of active type 1 plasminogen activator inhibitor. J Biol Chem 1994; 269: 2659-66.
    CrossrefPubMedGoogle Scholar
  • 39 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: 425-37.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Lawrence DA, Loskutoff DJ. Inactivation of plasminogen activator inhibitor by oxidants. Biochemistry 1986; 25: 6351-5.
    CrossrefPubMedGoogle Scholar
  • 41 Stefansson S, Muhammad S, Cheng XF. et al. Plasminogen activator inhibitor-1 contains a cryptic high affinity binding site for the low density lipoprotein receptor-related protein. J Biol Chem 1998; 273: 6358-66.
    CrossrefPubMedGoogle Scholar
  • 42 Loskutoff DJ. Regulation of PAI-1 gene expression. Fibrinolysis 1991; 5: 197-206.
    CrossrefPubMedGoogle Scholar
  • 43 van den Berg EA, Sprengers ED, Jaye M. et al. Regulation of plasminogen activator inhibitor-1 mRNA in human endothelial cells. Thromb Haemost 1988; 60: 63-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Schleef RR, Bevilacqua MP, Sawdey M. et al. Interleukin 1 (IL-1) and tumor necrosis factor (TNF) activation of vascular endothelium: Effects on plasminogen activator inhibitor (PAI-1) and tissue type plasminogen activator (tPA). J Biol Chem 1988; 263: 5797-803.
    CrossrefPubMedGoogle Scholar
  • 45 Abe M, Harpel JG, Metz CN. et al. An assay for transforming growth factor-beta using cells transfected with a plasminogen activator inhibitor-1 promoter-luciferase construct. Anal Biochem 1994; 216: 276-84.
    CrossrefPubMedGoogle Scholar
  • 46 Slivka SR, Loskutoff DJ. Platelets stimulate endothelial cells to synthesize type 1 plasminogen activator inhibitor. Evaluation of the role of transforming growth factor beta. Blood 1991; 77: 1013-9.
    CrossrefPubMedGoogle Scholar
  • 47 Irigoyen JP, Munoz-Canoves P, Montero L. et al. The plasminogen activator system: biology and regulation. Cell Mol Life Sci 1999; 56: 104-32.
    CrossrefPubMedGoogle Scholar
  • 48 Hou B, Eren M, Painter CA. et al. Tumor necrosis factor activates the human plasminogen activator inhibitor- 1 gene through a distal nuclear factor B site. J Biol Chem 2004; 279: 18127-36.
    CrossrefPubMedGoogle Scholar
  • 49 Kohler HP, Grant PJ. Plasminogen-activator inhibitor type 1 and coronary artery disease. N Engl J Med 2000; 342: 1792-801.
    CrossrefPubMedGoogle Scholar
  • 50 Francis CW. Plasminogen activator inhibitor-1 levels and polymorphisms. Arch Pathol Lab Med 2002; 126: 1401-4.
    CrossrefPubMedGoogle Scholar
  • 51 Vermont C, de Groot R, Hazelzet J. Bench-to-bedside review: Genetic influences on meningococcal disease. Critical Care 2002; 6: 60-5.
    CrossrefPubMedGoogle Scholar
  • 52 Roest M, Banga JD. Editorial comment-- genetic make-up for increased PAI-1 expression protects against stroke. Stroke 2003; 34: 2828-9.
    CrossrefPubMedGoogle Scholar
  • 53 Tsirka SE, Gualandris A, Amaral DG. et al. Excitotoxin- induced neuronal degeneration and seizure are mediated by tissue plasminogen activator. Nature 1995; 377: 340-4.
    CrossrefPubMedGoogle Scholar
  • 54 Lauffenburger DA, Horwitz AF. Cell migration: a physically integrated molecular process. Cell 1996; 84: 359-69.
    CrossrefPubMedGoogle Scholar
  • 55 Deng G, Curriden SA, Wang S. et al. Is plasminogen activator inhibitor-1 the molecular switch that governs urokinase receptor-mediated cell adhesion and release?. J Cell Biol 1996; 134: 1563-71.
    CrossrefPubMedGoogle Scholar
  • 56 Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha V beta 3 binding to vitronectin. Nature 1996; 383: 441-3.
    CrossrefPubMedGoogle Scholar
  • 57 Kjoller L, Kanse SM, Kirkegaard T. et al. Plasminogen activator inhibitor-1 represses integrin- and vitronectin- mediated cell migration independently of its function as an inhibitor of plasminogen activation. Exp Cell Res 1997; 232: 420-9.
    CrossrefPubMedGoogle Scholar
  • 58 Palmieri D, Lee JW, Juliano RL. et al. Plasminogen activator inhibitor-1 and –3 increase cell adhesion and motility of MDA-MB-435 breast cancer cells. J Biol Chem 2002; 277: 40950-7.
    CrossrefPubMedGoogle Scholar
  • 59 Wei Y, Lukashev M, Simon I D. et al. Regulation of integrin function by the urokinase receptor. Science 1996; 273: 1551-5.
    CrossrefPubMedGoogle Scholar
  • 60 Felding-Habermann B, Cheresh DA. Vitronectin and its receptors. Curr Opin Cell Biol 1993; 5: 864-8.
    CrossrefPubMedGoogle Scholar
  • 61 Waltz DA, Natkin LR, Fujita RM. et al. Plasmin and plasminogen activator inhibitor type 1 promote cellular motility by regulating the interaction between the urokinase receptor and vitronectin. J Clin Invest 1997; 100: 58-67.
    CrossrefPubMedGoogle Scholar
  • 62 Deng G, Curriden SA, Hu G. et al. Plasminogen activator inhibitor-1 regulates cell adhesion by binding to the somatomedin B domain of vitronectin. J Cell Physiol 2001; 189: 23-33.
    CrossrefPubMedGoogle Scholar
  • 63 Okumura Y, Kamikubo Y, Curriden SA. et al. Kinetic analysis of the interaction between vitronectin and the urokinase receptor. J Biol Chem 2002; 277: 9395-404.
    CrossrefPubMedGoogle Scholar
  • 64 Czekay RP, Aertgeerts K, Curriden SA. et al. Plasminogen activator inhibitor-1 detaches cells from extracellular matrices by inactivating integrins. J Cell Biol 2003; 160: 781-91.
    CrossrefPubMedGoogle Scholar
  • 65 Stefansson S, Lawrence DA. Old dogs and new tricks: proteases, inhibitors, and cell migration. Sci STKE 2003; 2003: e24
    CrossrefPubMedGoogle Scholar
  • 66 Bastholm L, Nielsen MH, De Mey J. et al. Confocal fluorescence microscopy of urokinase plasminogen activator receptor and cathepsin D in human MDAMB- 231 breast cancer cells migrating in reconstituted basement membrane. Biotech Histochem 1994; 69: 61-7.
    CrossrefPubMedGoogle Scholar
  • 67 Mondino A, Resnati M, Blasi F. Structure and function of the urokinase receptor. Thromb Haemost 1999; 82 (Suppl. 01) 19-22
    Article in Thieme ConnectPubMedGoogle Scholar
  • 68 Wei Y, Waltz DA, Rao N. et al. Identification of the urokinase receptor as an adhesion receptor for vitronectin. J Biol Chem 1994; 269: 32380-8.
    CrossrefPubMedGoogle Scholar
  • 69 Chapman HA, Wei Y. Protease crosstalk with integrins: the urokinase receptor paradigm. Thromb Haemost 2001; 86: 124-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 70 Ossowski L, Aguirre-Ghiso JA. Urokinase receptor and integrin partnership: coordination of signaling for cell adhesion, migration and growth. Curr Opin Cell Biol 2000; 12: 613-20.
    CrossrefPubMedGoogle Scholar
  • 71 Kjoller L. The urokinase plasminogen activator receptor in the regulation of the actin cytoskeleton and cell motility. Biol Chem 2002; 383: 5-19.
    CrossrefPubMedGoogle Scholar
  • 72 Kirchheimer JC, Binder BR, Remold HG. Matrixbound plasminogen activator inhibitor type 1 inhibits the invasion of human monocytes into interstitial tissue. J Immunol 1990; 145: 1518-22.
    CrossrefPubMedGoogle Scholar
  • 73 Degryse B, Neels JG, Czekay RP. et al. The low density lipoprotein receptor-related protein is a motogenic receptor for plasminogen activator inhibitor-1. J Biol Chem 2004; 279: 22595-604.
    CrossrefPubMedGoogle Scholar
  • 74 Chazaud B, Ricoux R, Christov C. et al. Promigratory effect of plasminogen activator inhibitor-1 on invasive breast cancer cell populations. Am J Pathol 2002; 160: 237-46.
    CrossrefPubMedGoogle Scholar
  • 75 Stahl A, Mueller BM. Melanoma cell migration on vitronectin: regulation by components of the plasminogen activation system. Int J Cancer 1997; 71: 116-22.
    CrossrefPubMedGoogle Scholar
  • 76 Fay WP, Parker AC, Condrey LR. et al. 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: 204-8.
    CrossrefPubMedGoogle Scholar
  • 77 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: 2756-60.
    CrossrefPubMedGoogle Scholar
  • 78 Erickson LA, Fici GJ, Lund JE. et al. Development of venous occlusions in mice transgenic for the plasminogen activator inhibitor-1 gene. Nature 1990; 346: 74-6.
    CrossrefPubMedGoogle Scholar
  • 79 Eren M, Painter CA, Atkinson JB. et al. Age-dependent spontaneous coronary arterial thrombosis in transgenic mice that express a stable form of human plasminogen activator inhibitor-1. Circulation 2002; 106: 491-6.
    CrossrefPubMedGoogle Scholar
  • 80 Yamamoto K, Takeshita K, Shimokawa T. et al. Plasminogen activator inhibitor-1 is a major stressregulated gene: implications for stress-induced thrombosis in aged individuals. Proc Natl Acad Sci U S A 2002; 99: 890-5.
    CrossrefPubMedGoogle Scholar
  • 81 Konstantinides S, Schafer K, Thinnes T. et al. Plasminogen activator inhibitor-1 and its cofactor vitronectin stabilize arterial thrombi after vascular injury in mice. Circulation 2001; 103: 576-83.
    CrossrefPubMedGoogle Scholar
  • 82 Eitzman DT, Westrick RJ, Nabel EG. et al. Plasminogen activator inhibitor-1 and vitronectin promote vascular thrombosis in mice. Blood 2000; 95: 577-80.
    CrossrefPubMedGoogle Scholar
  • 83 Meade TW, Ruddock V, Stirling Y. et al. Fibrinolytic activity, clotting factors, and long-term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342: 1076-9.
    CrossrefPubMedGoogle Scholar
  • 84 Hamsten A, de Faire U, Walldius G. et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet 1987; 2: 3-9.
    CrossrefPubMedGoogle Scholar
  • 85 Angleton P, Chandler WL, Schmer G. Diurnal variation of tissue-type plasminogen activator and its rapid inhibitor (PAI-1). Circulation 1989; 79: 101-6.
    CrossrefPubMedGoogle Scholar
  • 86 Andreotti F, Davies GJ, Hackett DR. et al. Major circadian fluctuations in fibrinolytic factors and possible relevance to time of onset of myocardial infarction, sudden cardiac death and stroke. Am J Cardiol 1988; 62: 635-7.
    CrossrefPubMedGoogle Scholar
  • 87 Kluft C, Verheijen JH, Jie AF. et al. The postoperative fibrinolytic shutdown: a rapidly reverting acute phase pattern for the fast-acting inhibitor of tissue-type plasminogen activator after trauma. Scand J Clin Lab Invest 1985; 45: 605-10.
    CrossrefPubMedGoogle Scholar
  • 88 Kruithof EK, Tran-Thang C, Gudinchet A. et al. Fibrinolysis in pregnancy: a study of plasminogen activator inhibitors. Blood 1987; 69: 460-6.
    CrossrefPubMedGoogle Scholar
  • 89 Hack CE. Fibrinolysis in disseminated intravascular coagulation. Semin Thromb Hemost 2001; 27: 633-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 90 Pralong G, Calandra T, Glauser MP. et al. Plasminogen activator inhibitor 1: a new prognostic marker in septic shock. Thromb Haemost 1989; 61: 459-62.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 91 Vivien D, Buisson A. Serine protease inhibitors: novel therapeutic targets for stroke?. J Cereb Blood Flow Metab 2000; 20: 755-64.
    CrossrefPubMedGoogle Scholar
  • 92 Wang YF, Tsirka SE, Strickland S. et al. Tissue plasminogen activator (tPA) increases neuronal damage after focal cerebral ischemia in wild-type and tPA-deficient mice. Nat Med 1998; 4: 228-31.
    CrossrefPubMedGoogle Scholar
  • 93 Fuster V, Badimon L, Badimon JJ. et al. The pathogenesis of coronary artery disease and the acute coronary syndromes (2). N Engl J Med 1992; 326: 310-8.
    CrossrefPubMedGoogle Scholar
  • 94 Young JL, Libby P, Schonbeck U. Cytokines in the pathogenesis of atherosclerosis. Thromb Haemost 2002; 88: 554-67.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 95 Dichtl W, Stiko A, Eriksson P. et al. Oxidized LDL and lysophosphatidylcholine stimulate plasminogen activator inhibitor-1 expression in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 1999; 19: 3025-32.
    CrossrefPubMedGoogle Scholar
  • 96 Sawa H, Lundgren C, Sobel BE. et al. Increased intramural expression of plasminogen activator inhibitor type 1 after balloon injury: a potential progenitor of restenosis. J Am Coll Cardiol 1994; 24: 1742-8.
    CrossrefPubMedGoogle Scholar
  • 97 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: 6998-7002.
    CrossrefPubMedGoogle Scholar
  • 98 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: 1090-100.
    CrossrefPubMedGoogle Scholar
  • 99 Schafer K, Muller 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: 2097-103.
    CrossrefPubMedGoogle Scholar
  • 100 Robbie LA, Booth NA, Brown AJ. et al. Inhibitors of fibrinolysis are elevated in atherosclerotic plaque. Arterioscler Thromb Vasc Biol 1996; 16: 539-45.
    CrossrefPubMedGoogle Scholar
  • 101 Burke AP, Kolodgie FD, Farb A. et al. Healed plaque ruptures and sudden coronary death: evidence that subclinical rupture has a role in plaque progression. Circulation 2001; 103: 934-40.
    CrossrefPubMedGoogle Scholar
  • 102 Konstantinides S, Schafer K, Loskutoff DJ. Do PAI-1 and vitronectin promote or inhibit neointima formation? The exact role of the fibrinolytic system in vascular remodeling remains uncertain. Arterioscler Thromb Vasc Biol 2002; 22: 1943-5.
    CrossrefPubMedGoogle Scholar
  • 103 Zhu Y, Farrehi PM, Fay WP. Plasminogen activator inhibitor type 1 enhances neointima formation after oxidative vascular injury in atherosclerosis-prone mice. Circulation 2001; 103: 3105-10.
    CrossrefPubMedGoogle Scholar
  • 104 Tanaka S, Koyama H, Ichii T. et al. Fibrillar collagen regulation of plasminogen activator inhibitor-1 is involved in altered smooth muscle cell migration. Arterioscler Thromb Vasc Biol 2002; 22: 1573-8.
    CrossrefPubMedGoogle Scholar
  • 105 Carmeliet P, Moons L, Lijnen R. et al. Inhibitory role of plasminogen activator inhibitor-1 in arterial wound healing and neointima formation: a gene targeting and gene transfer study in mice. Circulation 1997; 96: 3180-91.
    CrossrefPubMedGoogle Scholar
  • 106 Loskutoff DJ, Quigley JP. PAI-1, fibrosis, and the elusive provisional fibrin matrix. J Clin Invest 2000; 106: 1441-3.
    CrossrefPubMedGoogle Scholar
  • 107 Oda T, Jung YO, Kim HS. et al. PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 2001; 60: 587-96.
    CrossrefPubMedGoogle Scholar
  • 108 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: 232-7.
    CrossrefPubMedGoogle Scholar
  • 109 Huang Y, Haraguchi M, Lawrence DA. et al. A mutant, noninhibitory plasminogen activator inhibitor type 1 decreases matrix accumulation in experimental glomerulonephritis. J Clin Invest 2003; 112: 379-88.
    CrossrefPubMedGoogle Scholar
  • 110 Yamamoto T, Noble NA, Cohen AH. et al. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int 1996; 49: 461-9.
    CrossrefPubMedGoogle Scholar
  • 111 Bertozzi P, Astedt B, Zenzius L. et al. Depressed bronchoalveolar urokinase activity in patients with adult respiratory distress syndrome. N Engl J Med 1990; 322: 890-7.
    CrossrefPubMedGoogle Scholar
  • 112 Reaven P. Metabolic syndrome. J Insur Med 2004; 36: 132-42.
    PubMedGoogle Scholar
  • 113 Juhan-Vague I, Alessi MC, Mavri A. et al. Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. J Thromb Haemost 2003; 1: 1575-9.
    CrossrefPubMedGoogle Scholar
  • 114 Morange PE, Aubert J, Peiretti F. et al. Glucocorticoids and insulin promote plasminogen activator in- hibitor 1 production by human adipose tissue. Diabetes 1999; 48: 890-5.
    CrossrefPubMedGoogle Scholar
  • 115 Lundgren CH, Brown SL, Nordt TK. et al. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. A potential pathogenetic link between obesity and cardiovascular disease. Circulation 1996; 93: 106-10.
    CrossrefPubMedGoogle Scholar
  • 116 Crandall DL, Groeling TM, Busler DE. et al. Release of PAI-1 by human preadipocytes and adipocytes independent of insulin and IGF-1. Biochem Biophys Res Commun 2000; 279: 984-8.
    CrossrefPubMedGoogle Scholar
  • 117 Alessi MC, Peiretti F, Morange P. et al. Production of plasminogen activator inhibitor 1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 1997; 46: 860-7.
    CrossrefPubMedGoogle Scholar
  • 118 Samad F, Loskutoff DJ. Tissue distribution and regulation of plasminogen activator inhibitor-1 in obese mice. Mol Med 1996; 2: 568-2.
    CrossrefPubMedGoogle Scholar
  • 119 Schafer K, Fujisawa K, Konstantinides S. et al. 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: 1840-2.
    CrossrefPubMedGoogle Scholar
  • 120 Ma L, Mao SL, Taylor KL. et al. Prevention of obesity and insulin resistance in mice lacking plasminogen activator inhibitor 1. Diabetes 2004; 53: 336-46.
    CrossrefPubMedGoogle Scholar
  • 121 Morange PE, Lijnen HR, Alessi MC. et al. 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: 1150-4.
    CrossrefPubMedGoogle Scholar
  • 122 Nordt TK, Sawa H, Fujii S. et al. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation 1995; 91: 764-70.
    CrossrefPubMedGoogle Scholar
  • 123 Samad F, Pandey M, Bell PA. et al. Insulin continues to induce plasminogen activator inhibitor 1 gene expression in insulin-resistant mice and adipocytes. Mol Med 2000; 6: 680-92.
    CrossrefPubMedGoogle Scholar
  • 124 Carmassi F, Morale M, Ferrini L. et al. Local insulin infusion stimulates expression of plasminogen activator inhibitor-1 and tissue-type plasminogen activator in normal subjects. Am J Med 1999; 107: 344-50.
    CrossrefPubMedGoogle Scholar
  • 125 Juhan-Vague I, Roul C, Alessi MC. et al. Increased plasminogen activator inhibitor activity in non insulin dependent diabetic patients--relationship with plasma insulin. Thromb Haemost 1989; 61: 370-3.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 126 Mavri A, Stegnar M, Krebs M. et al. Impact of adipose tissue on plasma plasminogen activator inhibitor- 1 in dieting obese women. Arterioscler Thromb Vasc Biol 1999; 19: 1582-7.
    CrossrefPubMedGoogle Scholar
  • 127 Ehrmann DA, Schneider DJ, Sobel BE. et al. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997; 82: 2108-16.
    PubMedGoogle Scholar
  • 128 Chen Y-Q, Su M, Walia RR. et al. Sp1 sites mediate activation of the Plasminogen Activator Inhibitor-1 promoter by glucose in vascular smooth muscle cells. J Biol Chem 1998; 273: 8225-31.
    CrossrefPubMedGoogle Scholar
  • 129 Panahloo A, Mohamed-Ali V, Andres C. et al. Effect of insulin versus sulfonylurea therapy on cardiovascular risk factors and fibrinolysis in type II diabetes. Metabolism 1998; 47: 637-43.
    CrossrefPubMedGoogle Scholar
  • 130 Skurk T, Lee YM, Hauner H. Angiotensin II and its metabolites stimulate PAI-1 protein release from human adipocytes in primary culture. Hypertension 2001; 37: 1336-40.
    CrossrefPubMedGoogle Scholar
  • 131 Brown NJ, Agirbasli M, Vaughan DE. Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension 1999; 34: 285-90.
    CrossrefPubMedGoogle Scholar
  • 132 Sundell IB, Nilsson TK, Hallmans G. et al. Interrelationships between plasma levels of plasminogen activator inhibitor, tissue plasminogen activator, lipoprotein (a), and established cardiovascular risk factors in a north Swedish population. Atherosclerosis 1989; 80: 9-16.
    CrossrefPubMedGoogle Scholar
  • 133 Nilsson J, Gafvels M, Musakka L. et al. VLDL activation of plasminogen activator inhibitor-1 (PAI-1) expression: involvement of the VLDL receptor. J Lipid Res 1999; 40: 913-9.
    CrossrefPubMedGoogle Scholar
  • 134 Bavenholm P, Proudler A, Silveira A. et al. Relationships of insulin and intact and split proinsulin to haemostatic function in young men with and without coronary artery disease. Thromb Haemost 1995; 73: 568-75.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 135 Duffy MJ, Reilly D, O'Grady P. et al. Tissuetype and urokinasetype plasminogen activator as prognostic markers in breast cancer. CRC Press; New York: 1995
    Google Scholar
  • 136 Foekens JA, Peters HA, Look MP. et al. The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients. Cancer Res 2000; 60: 636-43.
    PubMedGoogle Scholar
  • 137 Janicke F, Schmitt M, Graeff H. Clinical relevance of the urokinase-type and tissue-type plasminogen activators and of their type 1 inhibitor in breast cancer. Semin Thromb Hemost 1991; 17: 303-12.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 138 Harbeck N, Kates RE, Gauger K. et al. Urokinasetype plasminogen activator (uPA) and its inhibitor PAI-I: novel tumor-derived factors with a high prognostic and predictive impact in breast cancer. Thromb Haemost 2004; 91: 450-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 139 Offersen BV, Nielsen BS, Hoyer-Hansen G. et al. The myofibroblast is the predominant plasminogen activator inhibitor-1-expressing cell type in human breast carcinomas. Am J Pathol 2003; 163: 1887-99.
    CrossrefPubMedGoogle Scholar
  • 140 Pyke C, Kristensen P, Ralfkiaer E. et al. The plasminogen activation system in human colon cancer: messenger RNA for the inhibitor PAI-1 is located in endothelial cells in the tumor stroma. Cancer Res 1991; 51: 4067-71.
    PubMedGoogle Scholar
  • 141 Sappino AP, Belin D, Huarte J. et al. Differential protease expression by cutaneous squamous and basal cell carcinomas. J Clin Invest 1991; 88: 1073-9.
    CrossrefPubMedGoogle Scholar
  • 142 Reilly D, Christensen L, Duch M. et al. Type-1 plasminogen activator inhibitor in human breast carcinomas. Int J Cancer 1992; 50: 208-14.
    CrossrefPubMedGoogle Scholar
  • 143 Curino A, Mitola DJ, Aaronson H. et al. Plasminogen promotes sarcoma growth and suppresses the accumulation of tumor-infiltrating macrophages. Oncogene 2002; 21: 8830-42.
    CrossrefPubMedGoogle Scholar
  • 144 Bajou K, Noel A, Gerard RD. et al. Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization. Nat Med 1998; 4: 923-8.
    CrossrefPubMedGoogle Scholar
  • 145 McMahon GA, Petitclerc E, Stefansson S. et al. Plasminogen activator inhibitor-1 regulates tumor growth and angiogenesis. J Biol Chem 2001; 276: 33964-8.
    CrossrefPubMedGoogle Scholar
  • 146 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: 147-54.
    CrossrefPubMedGoogle Scholar
  • 147 Kono S, Rao JS, Bruner JM. et al. Immunohistochemical localization of plasminogen activator inhibitor type 1 in human brain tumors. J Neuropathol Exp Neurol 1994; 53: 256-62.
    CrossrefPubMedGoogle Scholar
  • 148 Prendergast GC, Diamond LE, Dahl D. et al. The c-myc-regulated gene mr1 encodes plasminogen activator inhibitor 1. Mol Cell Biol 1991; 10: 1265-9.
    PubMedGoogle Scholar
  • 149 Podor TJ, Peterson CB, Lawrence DA. et al. Type 1 plasminogen activator inhibitor binds to fibrin via vitronectin. J Biol Chem 2000; 275: 19788-94.
    CrossrefPubMedGoogle Scholar