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Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and

Mitali Das1, Sujay Subbayya Ithychanda1, Edward F Plow1

  • 1Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

Biomolecules
|February 25, 2022
PubMed

Insights

Histone 2B (H2B) mediates plasminogen-induced endothelial cell migration, crucial for wound healing and angiogenesis. Blocking H2B with an antibody inhibits this migration, similar to Protease-Activated Receptor (PAR) antagonists.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Plasminogen and its receptors influence various cell responses.
  • Histone 2B (H2B) is known to be important in macrophage function.
  • The role of H2B in plasminogen-driven endothelial cell migration is not understood.

Purpose of the Study:

  • To investigate the role of Histone 2B (H2B) in plasminogen-induced endothelial cell migration.
  • To determine if H2B interacts with Protease-Activated Receptors (PARs) in endothelial cells.
  • To elucidate the mechanism linking plasminogen to endothelial cell functions like wound healing and angiogenesis.

Main Methods:

  • Endothelial cell migration assays were performed with and without plasminogen.
  • Protease-Activated Receptor-1 (PAR1) and Protease-Activated Receptor-2 (PAR2) antagonists were used to block receptor activity.
  • An antibody against H2B was employed to block plasminogen binding.
  • Pull-down assays were conducted to assess protein-protein interactions between H2B, PAR1, PAR2, β3 integrin, clathrin adaptor protein AP2µ, and β-arrestin2.

Main Results:

  • Plasminogen significantly enhanced endothelial cell migration.
  • This enhancement was inhibited by PAR1 and PAR2 antagonists.
  • H2B was present on endothelial cells, and an antibody blocking H2B-plasminogen binding also inhibited migration.
  • H2B formed complexes with PAR1 and PAR2, but not β3 integrin.
  • H2B associated with clathrin adaptor protein AP2µ and β-arrestin2, components of PAR internalization/signaling pathways.

Conclusions:

  • Histone 2B (H2B) is a key mediator of plasminogen-induced endothelial cell migration.
  • H2B interacts with PAR1 and PAR2, linking plasminogen to cellular responses.
  • The findings provide a mechanism for plasminogen's role in wound healing and angiogenesis via H2B-PAR signaling pathways.
Keywords:
endothelial cellshistone 2Bmigrationplasminogenprotease-activated receptors

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