Характеристика гена ингибитора активатора плазминогена 1 типа (PAI-1) и его роль в развитии артериального тромбоза


DOI: https://dx.doi.org/10.18565/pharmateca.2023.9-10.53-60

Изможерова Н.В., Попов А.А., Антропова И.П., Кадников Л.И., Полянок А.О., Испавский В.Е.

Уральский государственный медицинский университет, кафедра фармакологии и клинической фармакологии, Екатеринбург, Россия
Ингибитор активатора плазминогена-1 (PAI-1) является основным физиологическим ингибитором фибринолитической системы in vivo. Результаты современных исследований не позволяют сформировать однозначное мнение о степени влияния уровня PAI-1 и его полиморфизма (4G/5G, 4G/4G) на частоту развития тромботических событий в артериальном русле. В связи с этим целью данного обзора является составление обобщающей характеристики свойств PAI-1, а также установление роли его полиморфизма в развитии тромбоза в зависимости от индивидуальных физиологических и этнических факторов, а также перспективных направлений в его дальнейшем изучении.

Литература


1. NCD Countdown 2030 collaborators. NCD Countdown 2030: pathways to achieving Sustainable Development Goal target 3.4. Lancet. 2020;396(10255):918–34. Doi: 10.1016/S0140-6736(20)31761-X.


2. Федеральная служба государственной статистики.


3. Khan S.S. The Central Role of PAI-1 in COVID-19: Thrombosis and beyond. Am J Respir Cell Mol Biol. 202;65(3):238–40. Doi: 10.1165/rcmb.2021-0208ED.


4. Borczuk A.C., Salvatore S.P., Seshan S.V., et al. COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and New York City. Mod Pathol. 2020;33(11):2156–68. Doi: 10.1038/s41379-020-00661-1.


5. Whyte C.S., Simpson M., Morrow G.B., et al. The suboptimal fibrinolytic response in COVID-19 is dictated by high PAI-1. J Thromb Haemost. 2022;20(10):2394–406. Doi: 10.1111/jth.15806.


6. Chapin J.C., Hajjar K.A. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29(1):17–24. Doi: 10.1016/j.blre.2014.09.003.


7. Fay W.P., Garg N., Sunkar M. Vascular functions of the plasminogen activation system. Arterioscler Thromb Vasc Biol. 2007;27:1231–37. Doi: 10.1161/ATVBAHA.107.140046.


8. Mutch N.J., Thomas L., Moore N.R., et al. TAFIa, PAI-1 and alpha-antiplasmin: complementary roles in regulating lysis of thrombi and plasma clots. J Thromb Haemost. 2007;5(4):812–17. Doi: 10.1111/j.1538-7836.2007.02430.x.


9. Cesari M., Pahor M., Incalzi R.A. Plasminogen activator inhibitor-1 (PAI-1): a key factor linking fibrinolysis and age-related subclinical and clinical conditions. Cardiovasc Ther. 2010;28(5):e72–91. Doi: 10.1111/j.1755-5922.2010.00171.x.


10. Declerck P.J., Gills A. Three decades of research on plasminogen activator inhibitor-1: a multifaceted serpin. Semin Thromb Hemost. 2013;39(4):356–64. Doi: 10.1055/s-0033-1334487.


11. Morange P.E., Saut N., Alessi M.C., et al. Association of plasminogen activator inhibitor (PAI)-1 (SERPINE1) SNPs with myocardial infarction, plasma PAI-1, and metabolic parameters: the HIFMECH study. Arterioscler Thromb Vasc Biol. 2007;27(10):2250–57. Doi: 10.1161/ATVBAHA.107.149468.


12. Aso Y. Plasminogen activator inhibitor (PAI)-1 in vascular inflammation and thrombosis. Front Biosci. 2007;12:2957–66. Doi: 10.2741/2285.


13. Loskutoff D.J., Samad F. The adipocyte and hemostatic balance in obesity: studies of PAI-1. Arterioscler Thromb Vasc Biol. 1998;18(1):1–6. Doi: 10.1161/01.atv.18.1.1.


14. Szegedi I., Nagy A., Székely E.G., et al. PAI-1 5G/5G genotype is an independent risk of intracranial hemorrhage in post-lysis stroke patients. Ann Clin Transl Neurol. 2019;6(11):2240–50. Doi: 10.1002/acn3.50923.


15. Loskutoff D.J., Van Mourik J.A., Erickson L.A., Lawrence D. Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells. Proc Natl Acad Sci USA. 1983;80:2956–60. Doi: 10.1073/pnas.80.10.2956.


16. Zorio E., Gilabert-Estelles J., Espana F., et al. Fibrinolysis: the key to new pathogenetic mechanisms. Curr Med Chem. 2008;15:923–29. URL: Doi: 10.2174/092986708783955455.


17. Sillen M., Declerck P.J. A Narrative Review on Plasminogen Activator Inhibitor-1 and Its (Patho)Physiological Role: To Target or Not to Target? Int J Mol Sci. 2021;22(5):2721. Doi: 10.3390/ijms22052721.


18. Gils A., Pedersen K.E., Skottrup P., et al. Biochemical importance of glycosylation of plasminogen activator inhibitor-1. Thromb Haemost. 2003;90:206–17. Doi: 10.1160/TH03-01-0034.


19. Gettins P.G., Olson S.T. Inhibitory serpins. New insights into their folding, polymerization, regulation and clearance. Biochem J. 2016;473:2273–93. Doi: 10.1042/BCJ20160014.


20. Brogren H., Wallmark K., Deinum J., et al. Platelets Retain High Levels of Active Plasminogen Activator Inhibitor 1. PLoS One. 2011;6(11):e26762. Doi: 10.1371/journal.pone.0026762.


21. Thompson L.C., Goswami S., Ginsberg D.S., et al. Metals affect the structure and activity of human plasminogen activator inhibitor-1. I. Modulation of stability and protease inhibition. Protein Sci. 2010;20:353–65. Doi: 10.1002/pro.568.


22. Tofler G., Massaro J., O’Donnell C., et al. Plasminogen activator inhibitor and the risk of cardiovascular disease: The Framingham Heart Study. Thromb Res. 2016;140:30–5. Doi: 10.1016/j.thromres.2016.02.002.


23. Schar C.R., Jensen J.K., Christensen A., et al. Characterization of a site on PAI-1 that binds to vitronectin outside of the somatomedin B domain. J Biol Chem. 2008;283(42):28487–96. Doi: 10.1074/jbc.M804257200.


24. Brogren H., Karlsson L., Andersson M., et al. Platelets synthesize large amounts of active plasminogen activator inhibitor 1. Blood. 2004;104:3943–8. Doi: 10.1182/blood-2004-04-1439.


25. Napolitano F., Montuori N. Role of Plasminogen Activation System in Platelet Pathophysiology: Emerging Concepts for Translational Applications. Int J Mol Sci. 2022;23(11):6065. Doi: 10.3390/ijms23116065.


26. Morrow G.B., Whyte C.S., Mutch N.J. Functional plasminogen activator inhibitor 1 is retained on the activated platelet membrane following platelet activation. Haematologica. 2020;105(12):2824–33. Doi: 10.3324/haematol.2019.230367.


27. Torr-Brown S.R., Sobel B.E. Attenuation of thrombolysis by release of plasminogen activator inhibitor type-1 from platelets. Thromb Res. 1993;72:413–21. Doi: 10.1016/0049-3848(93)90241-F.


28. Huntington J.A., Read R.J., Carrell R.W. Structure of a serpin–protease complex shows inhibition by deformation. Na. Cell Biol. 2000;407:923–26. Doi: 10.1038/35038119.


29. Perron M.J., Blouse G.E., Shore J.D. Distortion of the Catalytic Domain of Tissue-type Plasminogen Activator by Plasminogen Activator Inhibitor-1 Coincides with the Formation of Stable Serpin-Proteinase Complexes. J Biol Chem. 2003;278:48197–203. Doi: 10.1074/jbc.M306184200.


30. Zhang X., Cai X., Pan J. Correlation Between PAI-1 Gene 4G/5G Polymorphism and the Risk of Thrombosis in Ph Chromosome-Negative Myeloproliferative Neoplasms. Clin Appl Thromb Hemost. 2020;26:1076029620935207. Doi: 10.1177/1076029620935207.


31. Rylander A.-C.J., Lindgren A., Deinum J., et al. Fibrinolysis inhibitors in plaque stability: A morphological association of PAI-1 and TAFI in advanced carotid plaque. J Thromb Haemost. 2017;15:758–69. Doi: 10.1111/jth.13641.


32. Ellulu M.S., Patimah I., Khaza’Ai H., et al. Obesity and inflammation: The linking mechanism and the complications. Arch Med Sci. 2017;4:851–63. Doi: 10.5114/aoms.2016.58928.


33. Rega G., Kaun C., Weiss T., et al. Inflammatory Cytokines Interleukin-6 and Oncostatin M Induce Plasminogen Activator Inhibitor-1 in Human Adipose Tissue. Circ. 2005;111:1938–45. Doi: 10.1161/01.CIR.0000161823.55935.BE.


34. Iwasaki H., Okamoto R., Kato S., et al. High glucose induces plasminogen activator inhibitor-1 expression through Rho/Rho-kinase-mediated NF-κB activation in bovine aortic endothelial cells. Atherosclerosis. 2008;196:22–8. Doi: 10.1016/j.atherosclerosis.2006.12.025.


35. Levine J.A., Oleaga C., Eren M., et al. Role of PAI-1 in hepatic steatosis and dyslipidemia. Sc. Rep. 2021;11:1–13. Doi: 10.1038/s41598-020-79948-x.


36. Raji M.A., Al Snih S., Ray L.A., et al. Cognitive status and incident disability in older Mexican Americans: findings from the Hispanic established population for the epidemiological study of the elderly. Eth. Dis. 2004;14:26–31.


37. Lutsey P.L., Cushman M., Steffen L.M., et al. Plasma hemostatic factors and endothelial markers in four racial/ethnic groups: the MESA study. . Throm. Haemost. 2006;4:2629–35. Doi: 10.1111/j.1538-7836.2006.02237.x.


38. Sillen M., Declerck P.J. Targeting PAI-1 in Cardiovascular Disease: Structural Insights Into PAI-1 Functionality and Inhibition. Fron. Cardiovas. Med. 2020;7:622473. Doi: 10.3389/fcvm.2020.622473.


39. Oh J., An H.J., Kim J.O., et al. Association between Five Common Plasminogen Activator Inhibitor-1 (PAI-1) Gene Polymorphisms and Colorectal Cancer Susceptibility. Int J Mol Sci. 2020;21(12):4334. Doi: 10.3390/ijms21124334.


40. Eriksson B.O., Gahm C., Halle M. Upregulation of Plasminogen Activator Inhibitor-1 in Irradiated Recipient Arteries and Veins from Free Tissue Transfer Reconstruction in Cancer Patients. Mediators Inflamm. 2018;2018:4058986. Doi: 10.1155/2018/4058986.


41. Festa A., D’Agostino R.Jr., Rich S.S., et al. Promoter (4G/5G) plasminogen activator inhibitor-1 genotype and plasminogen activator inhibitor-1 levels in blacks, Hispanics, and non-Hispanic whites: the Insulin Resistance Atherosclerosis Study. Circ. 2003;107(19):2422–27. Doi: 10.1161/01.CIR.0000066908.82782.3A.


42. Akhter M.S., Diswas A., Abdullah S.M., et al. The Role of PAI-1 4G/5G Promoter Polymorphism and Its Levels in the Development of Ischemic Stroke in Young Indian Population. Clin Appl Thromb Hemost. 2017;23(8):1071–76. Doi: 10.1177/1076029617705728.


43. Hultman K., Tjärnlund-Wolf A., Odeberg J., et al. Allele-specific transcription of the PAI-1 gene in human astrocytes. Thromb Haemost. 2010;104:998–1008. Doi: 10.1160/TH10-04-0243.


44. Eriksson P., Kallin B., van’t Hooft F.M., et al. Allele-specific increase in basal transcription of the plasminogen-activator inhibitor 1 gene is associated with myocardial infarction. Proc Natl Acad Sci USA. 1995;92(6):1851–55. Doi: 10.1073/pnas.92.6.1851.


45. Parpugga T.K., Tatarunas V., Skipskis V., et al. The Effect of PAI-1 4G/5G Polymorphism and Clinical Factors on Coronary Artery Occlusion in Myocardial Infarction. Dis Markers. 2015;2015:260101. Doi: 10.1155/2015/260101.


46. Fernandes K.S., Sandrim V.C. 4G/5G polymorphism modulates PAI-1 circulating levels in obese women. Mol Cell Biochem. 2012;364(1–2):299–301. Doi: 10.1007/s11010-012-1230-1.


47. Onalan O., Balta G., Oto A., et al. Plasminogen activator inhibitor-1 4G4G genotype is associated with myocardial infarction but not with stable coronary artery disease. J Thromb Thrombolysis. 2008;26(3):211–17. Doi: 10.1007/s11239-007-0083-z.


48. Nikolopoulos G.K., Bagos P.G., Tsangaris I., et al. The association between plasminogen activator inhibitor type 1 (PAI-1) levels, PAI-1 4G/5G polymorphism, and myocardial infarction: a Mendelian randomization meta-analysis. Clin Chem Lab Med. 2014;52(7):937–50. Doi: 10.1515/cclm-2013-1124.


49. Kumar S., Verma A.K., Sagar V., et al. Genotype Variations and Association between PAI-1 Promoter Region (4G/5G and -844G/A) and Susceptibility to Acute Myocardial Infarction and Chronic Stable Angina. Cardiol Res Pract. 2021;2021:5551031. Doi: 10.1155/2021/5551031.


50. García-González I.J., Valle Y., Sandoval-PintomE., et al. The -844 G>A PAI-1 Polymorphism Is Associated with Acute Coronary Syndrome in Mexican Population. Dis Markers. 2015;2015:460974. Doi: 10.1155/2015/460974.


51. Tjärnlund-Wolf A., Brogren H., Lo E.H., Wang X. Plasminogen activator inhibitor-1 and thrombotic cerebrovascular diseases. Stroke. 2012;43(10):2833–39. Doi: 10.1161/STROKEAHA.111.622217.


52. Wang J., Sun Z., Yang Y., et al. Association of laboratory parameters and genetic polymorphisms with ischemic stroke in Chinese Han population. Exp. Ther. Med. 2021;21(5):490. Doi: 10.3892/etm.2021.9921.


53. Jiménez-Gonzálezn M.C., Santiago-Germán D., Castillo-Henkel E.F., et al. Identification of genetic risk factors associated with ischaemic stroke in young Mexican patients. Neurologia (Engl Ed). 2021;36(5):337–45. Doi: 10.1016/j.nrleng.2018.01.011.


54. Hu X., Xin Zan X., Xie Z., et al. Association Between Plasminogen Activator Inhibitor-1 Genetic Polymorphisms and Stroke Susceptibility. Mol Neurobiol. 2017;54(1):328–41. Doi: 10.1007/s12035-015-9549-8.


55. Fernandez-Cadenas I., Del Rio-Espinola A., Rubiera M., et al. PAI-1 4G/5G polymorphism is associated with brain vessel reocclusion after successful fibrinolytic therapy in ischemic stroke patients. Int J Neurosci. 2010;120(4):245–51. Doi: 10.3109/00207451003597169.


56. Sarecka-Hujar B., Ilona Kopyta I., Michał Skrzypek M. Lack of Associations Between PAI-1 and FXIII Polymorphisms and Arterial Ischemic Stroke in Children: A Systematic Review and Meta-Analysis. Clin Appl Thromb Hemost. 2019;25:1076029619869500. Doi: 10.1177/1076029619869500.


57. Matsuyama T., Kubli S.P., Yoshinaga S.K., et al. An aberrant STAT pathway is central to COVID‐19. Cell Death Differ. 2020;27:3209–25. Doi: 10.1038/s41418-020-00633-7.


58. Lapić I., Antolic M.R., Horvat I., et al. Association of polymorphisms in genes encoding prothrombotic and cardiovascular risk factors with disease severity in COVID-19 patients: A pilot study. J Med Virol. 2022;94(8):3669–75. Doi: 10.1002/jmv.27774.


59. Han M., Pandey D. ZMPSTE24 Regulates SARS-CoV-2 Spike Protein–enhanced Expression of Endothelial PAI-1. Am J Respir Cell Mol Biol. 2021;65(3):300–8. Doi: 10.1165/rcmb.2020-0544OC.


60. Rapkiewicz A.V., Mai X., Carsons S.E., et al. Megakaryocytes and platelet-fibrin thrombi characterize multi-organ thrombosis at autopsy in COVID-19: A case series. EClinicalMedicine. 2020;24:100434. Doi: 10.1016/j.eclinm.2020.100434.


61. Lombardi C.M., Carubelli V., Iorio A., et al. Association of Troponin Levels With Mortality in Italian Patients Hospitalized With Coronavirus Disease 2019: Results of a Multicenter Study. JAMA. Cardiol. 2020;5(11):1274–80. Doi: 10.1001/jamacardio.2020.3538.


62. Zuo Y., Warnock M., Harbaugh A., et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor-1 in hospitalized COVID-19 patients. Sci Rep. 2021;11(1):1580. Doi: 10.1038/s41598-020-80010-z.


63. Morrow G.B., Mutch N.J. Past, Present, and Future Perspectives of Plasminogen Activator Inhibitor 1 (PAI-1). Semin Thromb Hemost. 2023;49(3):305–13. Doi: 10.1055/s-0042-1758791.


64. Marchenko V., Mukhametdinova D., Amosova I., et al. Influenza A(H1N1)pdm09 Virus Alters Expression of Endothelial Factors in Pulmonary Vascular Endothelium in Rats. Viruses. 2022;14(11):2518. Doi: 10.3390/v14112518.


65. Марченко В.А., Барашкова С.В., Зелинская И.А. и др.


66. Labeyrie P.E., Goulay R., Martinez de Lizarrondo S., et al. Vascular Tissue-Type Plasminogen Activator Promotes Intracranial Aneurysm Formation. Stroke. 2017;48(9):2574–82. Doi: 10.1161/STROKEAHA.117.017305.


67. Choi G.H., Cho S.H., An H.J., et al. Association between PAI-1 Polymorphisms and Ischemic Stroke in a South Korean Case-Control Cohort. Int J Mol Sci. 2023;24(9):8041. Doi: 10.3390/ijms24098041.


68. Oszajca K., Wroński K., Janiszewska G., et al. The study of t-PA, u-PA and PAI-1 genes polymorphisms in patients with abdominal aortic aneurysm. Mol Biol Rep. 2014;41(5):2859–64. Doi: 10.1007/s11033-014-3141-6.


Об авторах / Для корреспонденции


Автор для связи: Леонид Игоревич Кадников, аспирант кафедры фармакологии и клинической фармакологии, Уральский государственный медицинский университет, Екатеринбург, Россия; kadn-leonid@mail.ru


ORCID: 
Н.В. Изможерова (N.V. Izmozherova), https://orcid.org/0000-0001-7826-9657
А.А. Попов (A.A. Popov), https://orcid.org/0000-0001-6216-2468
И.П. Антропова (I.P. Antropova), https://orcid.org/0000-0002-9957-2505
Л.И. Кадников (L.I. Kadnikov), https://orcid.org/0000-0002-2623-2657
А.О. Полянок (A.O. Polyanok), https://orcid.org/0000-0003-1300-8768
В.Е. Испавский (V.E. Ispavsky), https://orcid.org/0000-0001-8152-6474


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