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Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation

C Urbich1, Z Mallat, A Tedgui

  • 1Molecular Cardiology, Department of Internal Medicine IV, University of Frankfurt, Frankfurt, Germany.

The Journal of Clinical Investigation
|November 21, 2001
PubMed

Insights

Shear stress, a blood flow force, prevents artery inflammation by increasing TNF receptor-associated factor-3 (TRAF-3). This mechanism inhibits CD40-induced endothelial cell activation, protecting blood vessels.

Area of Science:

  • Cardiovascular Biology
  • Inflammation Research
  • Endothelial Cell Biology

Background:

  • Atherosclerosis is an inflammatory arterial disease initiated by endothelial cell activation.
  • CD40 receptor stimulation is implicated in atherosclerosis development.
  • Endothelial shear stress is a key atheroprotective stimulus.

Purpose of the Study:

  • To investigate the protective mechanisms of endothelial shear stress against CD40 ligand-induced activation.
  • To identify molecular mediators involved in shear stress-mediated atheroprotection.

Main Methods:

  • Cultured endothelial cells were subjected to shear stress.
  • Expression levels of TNF receptor-associated factor-3 (TRAF-3) were analyzed.
  • Overexpression of TRAF-3 was performed to assess its functional impact.
  • Analysis of proinflammatory cytokine and tissue factor expression, and AP-1 DNA-binding activity.

Main Results:

  • Shear stress specifically upregulates TRAF-3 expression in endothelial cells.
  • TRAF-3 expression is elevated in areas of high shear stress overlying human atherosclerotic plaques.
  • Overexpression of TRAF-3 inhibits CD40-induced endothelial activation, including proinflammatory cytokine and tissue factor expression.
  • TRAF-3 overexpression blocks AP-1 DNA-binding activity.

Conclusions:

  • Upregulation of TRAF-3 is a novel mechanism by which shear stress inhibits CD40-induced endothelial activation.
  • TRAF-3 plays a critical role in preserving endothelial integrity under inflammatory conditions.
  • Targeting TRAF-3 may offer a therapeutic strategy for atherosclerosis.

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