Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Plasminogen Activator Inhibitor-1

  • Deniz Agirbasli
  • Mehmet AgirbasliEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101797


 Plasminogen activator inhibitor;  PAI;  PAI-1;  PLANH1;  Plasminogen activator inhibitor 1;  Serine (or cysteine) proteinase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1;  Serpin E1;  Serpin peptidase inhibitor, clade E (nexin, plasminogen activator inhibitor type 1), member 1;  SERPINE1

 BMAL-1: ARNTL; Aryl Hydrocarbon Receptor Nuclear Translocator Like

 Plasminogen activator inhibitor-2;  PAI-2: SERPINEB2; PLANH2; Plasminogen activator inhibitor-3; PAI-3: PCI; PLNH3; SERPINA5

 tPA: tissue plasminogen acitvator, PLAT; Plasminogen Activator, Tissue Type

 uPA: PLAU; Plasminogen Activator, urokinase-type plasminogen activator

Historical Background

The fibrinolysis complex includes a serine protease inhibitor (SERPIN), type-1 plasminogen activator inhibitor (PAI-1), and its target serine proteinases, the urokinase, and tissue-type plasminogen activators (uPA and tPA). As serine proteases, uPA and tPA coordinate various physiological functions,...

This is a preview of subscription content, log in to check access.


  1. Agirbasli M. Pivotal role of plasminogen-activator inhibitor 1 in vascular disease. Int J Clin Pract. 2005;59(1):102–6.  https://doi.org/10.1111/j.1742-1241.2005.00379.x.CrossRefPubMedGoogle Scholar
  2. Agirbasli D, Agirbasli M, Williams SM, Phillips 3rd JA. Interaction among 5,10 methylenetetrahydrofolate reductase, plasminogen activator inhibitor and endothelial nitric oxide synthase gene polymorphisms predicts the severity of coronary artery disease in Turkish patients. Coron Artery Dis. 2006;17(5):413–7.CrossRefPubMedGoogle Scholar
  3. 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;46:860–7.CrossRefPubMedGoogle Scholar
  4. 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
  5. Balsara RD, Ploplis VA. Plasminogen activator inhibitor-1: the double-edged sword in apoptosis. Thromb Haemost. 2008;100(6):1029–36.  https://doi.org/10.1160/TH08-07-0427.CrossRefPubMedPubMedCentralGoogle Scholar
  6. Berkenpas MB, Lawrence DA, Ginsburg D. Molecular evolution of plasminogen activator inhibitor-1 functional stability. EMBO J. 1995;14(13):2969–77.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Brogren H, Sihlbom C, Wallmark K, Lönn M, Deinum J, Karlsson L, et al. Heterogeneous glycosylation patterns of human PAI-1 may reveal its cellular origin. Thromb Res. 2008;122(2):271–81.  https://doi.org/10.1016/j.thromres.2008.04.008.CrossRefPubMedGoogle Scholar
  8. Bulut EC, Abueid L, Ercan F, Süleymanoğlu S, Ağırbaşlı M, Yeğen BÇ. Treatment with oestrogen-receptor agonists or oxytocin in conjunction with exercise protects against myocardial infarction in ovariectomized rats. Exp Physiol. 2016;101(5):612–27.  https://doi.org/10.1113/EP085708.CrossRefPubMedGoogle Scholar
  9. Busso N, Nicodeme E, Chesne C, Guillouzo A, Belin D, Hyafil F. Urokinase and type I plasminogen activator inhibitor production by normal human hepatocytes: modulation by inflammatory agents. Hepatology. 1994;20:186–90.PubMedGoogle Scholar
  10. Chandler WL. A kinetic model of the circulatory regulation of tissue plasminogen activator. Thromb Haemost. 1991;66(3):321–8.PubMedCrossRefGoogle Scholar
  11. Ciarleglio CM, Ryckman KK, Servick SV, Hida A, Robbins S, Wells N, et al. Genetic differences in human circadian clock genes among worldwide populations. J Biol Rhythm. 2008;23(4):330–40.  https://doi.org/10.1177/0748730408320284.CrossRefGoogle Scholar
  12. Coleman PL, Barouski PA, Gelehrter TD. The dexamethasone-induced inhibitor of fibrinolytic activity in hepatoma cells. A cellular product which specifically inhibits plasminogen activation. J Biol Chem. 1982;257:4260–4.PubMedGoogle Scholar
  13. Davis GL. Fibrinolysis inhibitors. Clin Lab Sci. 1997;10(4):212–8.PubMedGoogle Scholar
  14. Declerck PJ, De Mol M, Alessi MC, Baudner S, Paques EP, Preissner KT, 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):15454–61.PubMedGoogle Scholar
  15. Draxler DF, Medcalf RL. The fibrinolytic system-more than fibrinolysis? Transfus Med Rev. 2015;29(2):102–9.  https://doi.org/10.1016/j.tmrv.2014.09.006.CrossRefPubMedGoogle Scholar
  16. Durand MK, Bødker JS, Christensen A, Dupont DM, Hansen M, Jensen JK, et al. Plasminogen activator inhibitor-I and tumour growth, invasion, and metastasis. Thromb Haemost. 2004;91(3):438–49.  https://doi.org/10.1160/TH03-12-0784.CrossRefPubMedGoogle Scholar
  17. Elokdah H, Abou-Gharbia M, Hennan JK, McFarlane G, Mugford CP, Krishnamurthy G, et al. Tiplaxtinin, a novel, orally efficacious inhibitor of plasminogen activator inhibitor-1: design, synthesis, and preclinical characterization. J Med Chem. 2004;47(14):3491–4.  https://doi.org/10.1021/jm049766q.CrossRefPubMedGoogle Scholar
  18. 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;106:491–6.CrossRefPubMedGoogle Scholar
  19. Eren M, Painter CA, Gleaves LA, Schoenhard JA, Atkinson JB, Brown NJ, et al. Tissue- and agonist-specific regulation of human and murine plasminogen activator inhibitor-1 promoters in transgenic mice. J Thromb Haemost. 2003;1:2389–96.CrossRefPubMedGoogle Scholar
  20. Erickson LA, Ginsberg MH, Loskutoff DJ. Detection and partial characterization of an inhibitor of plasminogen activator in human platelets. J Clin Invest. 1984;74:1465–72.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Erickson LA, Schleef RR, Ny T, Loskutoff DJ. The fibrinolytic system of the vascular wall. Clin Haematol. 1985;14:513–30.PubMedGoogle Scholar
  22. Eriksson P, Kallin B, van’t Hooft FM, Bavenholm P, Hamsten A. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Nat Acad Sci. 1995;92:1851–5.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Flevaris P, Vaughan D. The role of plasminogen activator inhibitor type-1 in fibrosis. Semin Thromb Hemost. 2017 Mar;43(2):169–177.PubMedCrossRefGoogle Scholar
  24. Forsgren M, Raden B, Israelsson M, Larsson K, Heden LO. Molecular cloning and characterization of a full-length cDNA clone for human plasminogen. FEBS Lett. 1987;213(2):254–60.CrossRefPubMedGoogle Scholar
  25. Fortenberry YM. Plasminogen activator inhibitor-1 inhibitors: a patent review (2006-present). Expert Opin Ther Pat. 2013;23(7):801–15.  https://doi.org/10.1517/13543776.2013.782393.CrossRefPubMedGoogle Scholar
  26. Ginsburg D, Zeheb R, Yang AY, Rafferty UM, Andreasen PA, Nielsen L, et al. cDNA cloning of human plasminogen activator-inhibitor from endothelial cells. J Clin Invest. 1986;78:1673–80.  https://doi.org/10.1172/JCI112761.CrossRefPubMedPubMedCentralGoogle Scholar
  27. Gorlatova NV, Cale JM, Elokdah H, Li D, Fan K, Warnock M, et al. Mechanism of inactivation of plasminogen activator inhibitor-1 by a small molecule inhibitor. J Biol Chem. 2007;282(12):9288–96.  https://doi.org/10.1074/jbc.M611642200.CrossRefPubMedGoogle Scholar
  28. Hedstrom L. Serine protease mechanism and specificity. Chem Rev. 2002;102(12):4501–24.  https://doi.org/10.1021/cr000033x.CrossRefPubMedGoogle Scholar
  29. 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.PubMedGoogle Scholar
  30. Hennan JK, Morgan GA, Swillo RE, Antrilli TM, Mugford C, Vlasuk GP, et al. Effect of tiplaxtinin (PAI-039), an orally bioavailable PAI-1 antagonist, in a rat model of thrombosis. J Thromb Haemost. 2008;6(9):1558–64.  https://doi.org/10.1111/j.1538-7836.2008.03063.x.CrossRefPubMedGoogle Scholar
  31. Huang J, Sabater-Lleal M, Asselbergs FW, Tregouet D, Shin SY, Ding J, et al. Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. Blood. 2012;120(24):4873–81.  https://doi.org/10.1182/blood-2012-06-436188.CrossRefPubMedPubMedCentralGoogle Scholar
  32. Kaji H. Adipose tissue-derived plasminogen activator inhibitor-1 function and regulation. Compr Physiol. 2016;6(4):1873–96.  https://doi.org/10.1002/cphy.c160004.CrossRefPubMedGoogle Scholar
  33. Klinger KW, Winqvist R, Riccio A, Andreasen PA, Sartorio R, Nilesen LS, et al. Plasminogen activator inhibitor type 1 gene is located at region q21.3-q22 of chromosome 7 and genetically linked with cystic fibrosis. Proc Natl Acad Sci U S A. 1987;84(23):8548–52.PubMedPubMedCentralCrossRefGoogle Scholar
  34. Kortlever RM, Higgins PJ, Bernards R. Plasminogen activator inhibitor-1 is a critical downstream target of p53 in the induction of replicative senescence. Nat Cell Biol. 2006;8(8):877–84.  https://doi.org/10.1038/ncb1448.CrossRefPubMedPubMedCentralGoogle Scholar
  35. Kruithof EK. Plasminogen activator inhibitors – a review. Enzyme. 1988;40:113–21.CrossRefPubMedGoogle Scholar
  36. Kruithof EK, Trab-Thang C, Ransijn A, Bachmann F. Demonstration of a fast-acting inhibitor of plasminogen activators in human plasma. Blood. 1984;64:907–13.PubMedGoogle Scholar
  37. Kruithof EK, Vasalli JD, Schleuning WD, Mattaliano RJ, Bachmann F. Purification and characterization of a plasminogen activator inhibitor from the histiocytic lymphoma cell line U-937. J Biol Chem. 1986;261:11207–13.PubMedGoogle Scholar
  38. Kurnik PB. Circadian variation in the efficacy of tissue-type plasminogen activator. Circulation. 1995;91:1341–6.CrossRefPubMedGoogle Scholar
  39. Lademann U, Rømer MU, Jensen PB, Hofland KF, Larsen L, Christensen IJ, Brünner N. Malignant transformation of wild-type but not plasminogen activator inhibitor-1 gene-deficient fibroblasts decreases cellular sensitivity to chemotherapy-mediated apoptosis. Eur J Cancer. 2005;41(7):1095–100.CrossRefPubMedGoogle Scholar
  40. Lawrence DA, Olson ST, Palaniappan S, Ginsburg D. Engineering plasminogen activator inhibitor 1 mutants with increased functional stability. Biochemistry. 1994;33(12):3643–8.CrossRefPubMedGoogle Scholar
  41. Lindahl TL, Sigurdardottir O, Wiman B. Stability of plasminogen activator inhibitor 1 (PAI-1). Thromb Haemost. 1989;62(2):748–51.PubMedGoogle Scholar
  42. 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 USA. 1983;80:2956–60.PubMedPubMedCentralCrossRefGoogle Scholar
  43. Lundgren CH, Brown SL, Nordt TK, Sobel BE, Fujii S. Elaboration of type-1 plasminogen activator inhibitor from adipocytes. Circulation. 1996;93:106–10.CrossRefPubMedGoogle Scholar
  44. Maemura K, de la Monte SM, Chin MT, Layne MD, Hsieh CM, Yet SF, et al. CLIF, a novel cycle-like factor, regulates the circadian oscillation of plasminogen activator inhibitor-1 gene expression. J Biol Chem. 2000 Nov 24;275(47):36847–51.  https://doi.org/10.1074/jbc.C000629200.CrossRefPubMedGoogle Scholar
  45. Maemura K, Takeda N, Nagai R. Circadian rhythms in the CNS and peripheral clock disorders: role of the biological clock in cardiovascular diseases. J Pharmacol Sci. 2007;103(2):134–8.  https://doi.org/10.1254/jphs.FMJ06003X2.CrossRefPubMedGoogle Scholar
  46. Meijers JC, Herwald H. Protein C inhibitor. Semin Thromb Hemost. 2011;37(4):349–54.  https://doi.org/10.1055/s-0031-1276583.CrossRefPubMedGoogle Scholar
  47. Nordenhem A, Wiman B. Plasminogen activator inhibitor-1 (PAI-1) content in platelets from healthy individuals genotyped for the 4G/5G polymorphism in the PAI-1 gene. Scand J Clin Lab Invest. 1997;57:453–61.CrossRefPubMedGoogle Scholar
  48. Oishi K. Plasminogen activator inhibitor-1 and the circadian clock in metabolic disorders. Clin Exp Hypertens. 2009;31(3):208–19.  https://doi.org/10.1080/10641960902822468.CrossRefPubMedGoogle Scholar
  49. Pei X, Zhang J, Liu J. Clinical applications of nucleic acid aptamers in cancer. Mol Clin Oncol. 2014;2:341–8.  https://doi.org/10.3892/mco.2014.255.CrossRefPubMedPubMedCentralGoogle Scholar
  50. Placencio VR, DeClerck YA. Plasminogen activator inhibitor-1 in cancer: rationale and insight for future therapeutic testing. Cancer Res. 2015;75(15):2969–74.  https://doi.org/10.1158/0008-5472.CAN-15-0876.CrossRefPubMedPubMedCentralGoogle Scholar
  51. Rouch A, Vanucci-Bacque C, Bedos-Belval F, Baltas M. Small molecules inhibitors of plasminogen activator inhibitor-1—an overview. Eur J Med Chem. 2015;92:619–36.  https://doi.org/10.1016/j.ejmech.2015.01.010.CrossRefPubMedGoogle Scholar
  52. 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.  https://doi.org/10.1172/JCI115440.CrossRefPubMedPubMedCentralGoogle Scholar
  53. Schleef RR, Loskutoff DJ. Fibrinolytic system of vascular endothelial cells. Role of plasminogen activator inhibitors. Haemostasis. 1988;18:328–41.PubMedGoogle Scholar
  54. Schneider DJ, Chen Y, Sobel BE. The effect of plasminogen activator inhibitor type 1 on apoptosis. Thrombosis and haemostasis. 2008;100(6):1037–40 doi: 10.1160/TH08-04-0234.CrossRefPubMedGoogle Scholar
  55. Sobel B, Woodcock-Mitchell J, Schneider D, Holt R, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type-1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: a potential factor predisposing to thrombosis and its persistence. Circulation. 1998;97:2213–21.  https://doi.org/10.1161/01.CIR.97.22.2213.CrossRefPubMedGoogle Scholar
  56. Stefansson S, Lawrence DA. The serpin PAI-1 inhibits cell migration by blocking integrin alpha beta3 binding to vitronectin. Nature. 1996;383:441–3.  https://doi.org/10.1038/383441a0.CrossRefPubMedGoogle Scholar
  57. Taymaz H, Erarslan S, Oner ET, Alkan T, Ağirbaşli M, Kirdar B. Sequence variations within the genes related to hemostatic imbalance and their impact on coronary artery disease in Turkish population. Thromb Res. 2007;119(1):55–62.  https://doi.org/10.1016/j.thromres.2005.12.018.CrossRefPubMedGoogle Scholar
  58. Vaughan DE. PAI-1: a common denominator in cardiovascular disease. J Investig Med. 1998;46:370–6.PubMedGoogle Scholar
  59. Vaughan DE. PAI-1 and atherothrombosis. J Thromb Haemost. 2005;3:1879–83.  https://doi.org/10.1111/j.1538-7836.2005.01420.x.CrossRefPubMedGoogle Scholar
  60. Wang ZH, Ren WY, Zhu L, Hu LJ. Plasminogen activator inhibitor-1 regulates LPS induced inflammation in rat macrophages through autophagy activation. Sci World J. 2014;2014:189168.  https://doi.org/10.1155/2014/189168.CrossRefGoogle Scholar
  61. White MJ, Kodaman NM, Harder RH, Asselbergs FW, Vaughan DE, Brown NJ, et al. Genetics of plasminogen activator inhibitor-1 (PAI-1) in a Ghanaian population. PLoS One. 2015;10(8):e0136379.  https://doi.org/10.1371/journal.pone.0136379.CrossRefPubMedPubMedCentralGoogle Scholar
  62. Yasar Yildiz S, Kuru P, Toksoy Oner E, Agirbasli M. Functional stability of plasminogen activator inhibitor-1. Sci World J. 2014;2014:858293.  https://doi.org/10.1155/2014/858293.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Medical BiologyAcibadem University School of MedicineIstanbulTurkey
  2. 2.Department of CardiologyMedeniyet University Medical CenterIstanbulTurkey