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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Inflammation
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1445294
This article is part of the Research Topic Thromboinflammation in non-communicable and communicable diseases with a special emphasis on acute and long COVID View all 7 articles

The influence of 4G/5G polymorphism in the plasminogen-activator-inhibitor-1 promoter on COVID-19 severity and endothelial dysfunction

Provisionally accepted
Beate Heissig Beate Heissig 1,2*Ricardo Rios Ricardo Rios 3Tatiane Rios Tatiane Rios 3Yousef Salama Yousef Salama 4Satoshi Takahashi Satoshi Takahashi 5Eisuke Adachi Eisuke Adachi 6陽子 田部 陽子 田部 7Nobutaka Hattori Nobutaka Hattori 7TARO OSADA TARO OSADA 8Toshio Naito Toshio Naito 7Kazuhisa Takahashi Kazuhisa Takahashi 7Koichi Hattori Koichi Hattori 7Tetiana Yatsenko Tetiana Yatsenko 7
  • 1 School of Medicine, Juntendo University, Bunkyō, Japan
  • 2 Sportology Center, School of Medicine, Juntendo University, Bunkyō, Tokyo, Japan
  • 3 Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
  • 4 An-Najah National University, Nablus, Palestine
  • 5 Laboratory of Medical Proteomics, The Institute of Medical Science, The University Of Tokyo, Bunkyō, Tōkyō, Japan
  • 6 Institute of Medical Science, The University of Tokyo, Tokyo, Tokyo, Japan
  • 7 Juntendo University, Bunkyō, Tōkyō, Japan
  • 8 Juntendo University Urayasu Hospital, Urayasu, Chiba, Japan

The final, formatted version of the article will be published soon.

    Plasminogen activator inhibitor-1 (PAI-1) is linked to thrombosis and endothelial dysfunction in severe COVID-19. The +43 G>A PAI-1 and 4G/5G promoter polymorphism can influence PAI-1 expression. The 4G5G PAI-1 promoter gene polymorphism constitutes the 4G4G, 4G5G, and 5G5G genotypes.However, the impact of PAI-1 polymorphisms on disease severity or endothelial dysfunction remains unclear. Clinical data, sera, and peripheral blood mononuclear cells (PBMCs) of COVID-19 patients were studied. Comorbidities and clinical biomarkers did not correlate with genotypes in either polymorphism. However, differences between fibrinolytic factors and interleukin-1 (IL-1) were identified in genotypes of the 4G/5G but not the 43 G>A PAI polymorphism. Patients with the 4G4G genotype of the 4G/5G polymorphism showed high circulating PAI-1, mainly complexed with plasminogen activators, and low IL-1 and plasmin levels, indicating suppressed fibrinolysis. NFB was upregulated in PBMCs of COVID-19 patients with the 4G4G genotype.Mechanistically, IL-1 enhanced PAI-1 expression in 4G4G endothelial cells, preventing the generation of plasmin and cleavage products like angiostatin, soluble uPAR, and VCAM1. We identified inflammation-induced endothelial dysfunction coupled with fibrinolytic system overactivation as a risk factor for patients with the 5G5G genotype.

    Keywords: Plasminogen activator inhibitor-1, Fibrinolysis, Endothelial Cells, COVID-19, transcription factor, Coronavirus, Thrombosis, Inflammation

    Received: 07 Jun 2024; Accepted: 08 Aug 2024.

    Copyright: © 2024 Heissig, Rios, Rios, Salama, Takahashi, Adachi, 田部, Hattori, OSADA, Naito, Takahashi, Hattori and Yatsenko. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Beate Heissig, School of Medicine, Juntendo University, Bunkyō, Japan

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