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Updated: Oct 17, 2025

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Endothelial METTL3 (Methyltransferase-Like 3) Inhibits Fibrinolysis by Promoting PAI-1 (Plasminogen Activator

Qin Bai1, Yao Lu1, Yanhua Chen1

  • 1Department of Blood Transfusion, Daping Hospital, Army Medical University, Chongqing, China.

Arteriosclerosis, Thrombosis, and Vascular Biology
|October 14, 2021
PubMed
Abstract

Insights

Methyltransferase-like protein 3 (METTL3) regulates RNA methylation, impacting thrombosis. This study shows METTL3 suppresses fibrinolysis, offering a potential therapeutic target for blood clot disorders.

Area of Science:

  • Molecular Biology
  • Hematology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) modification, mediated by METTL3, is prevalent in eukaryotic mRNAs.
  • METTL3's role in thrombosis remains largely unexplored.
  • Endothelial cells play a key role in thrombosis regulation.

Purpose of the Study:

  • To investigate the function of METTL3 in endothelial cell-mediated thrombosis.
  • To elucidate the molecular mechanisms underlying METTL3's role in thrombosis.

Main Methods:

  • RNA sequencing and quantitative PCR in METTL3 knockdown endothelial cells.
  • RNA methylation sequencing and meRIP-qPCR to identify m6A sites.
  • Western blotting and chromatin immunoprecipitation assays.
  • In vivo studies using a lipopolysaccharide-induced endotoxemia mouse model.

Main Results:

  • METTL3 knockdown downregulated plasminogen activator inhibitor-1 (PAI-1) expression in endothelial cells.
  • METTL3 suppressed fibrinolysis by catalyzing m6A modification on JUN mRNA, promoting JUN protein expression.
  • JUN directly bound to the PAI-1 promoter.
  • Endothelial-specific METTL3 knockdown reduced plasma active PAI-1 and attenuated fibrin deposition in mice during endotoxemia.

Conclusions:

  • METTL3-mediated m6A modification is a critical regulator of fibrinolysis.
  • METTL3 plays a significant role in endothelial cell-mediated thrombosis.
  • Targeting METTL3 presents a potential therapeutic strategy for thrombotic disorders.
Keywords:
endothelial cellfibrinolysislipopolysaccharidesmethylationthrombosis

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