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

Carmen Urbich, Ziad Mallat, Alain Tedgui, Matthias Clauss, Andreas M. Zeiher, Stefanie Dimmeler

Research output: Contribution to journalArticle

70 Citations (Scopus)

Abstract

Atherosclerosis is an inflammatory disease of large arteries that is initiated through the activation of endothelium by proinflammatory mediators. CD40 receptor stimulation has been implicated in the pathogenesis of atherosclerosis. One of the most important atheroprotective stimuli is the viscous drag (shear stress) generated by the streaming blood acting on the endothelial monolayer. Here, we demonstrate that shear stress prevents CD40 ligand-induced endothelial cell activation, and we identify upregulation of TNF receptor-associated factor-3 (TRAF-3) as a potent CD40-inhibitory mechanism. Shear stress specifically upregulates TRAF-3 in cultured endothelial cells. Moreover, in the endothelial cells overlying human atherosclerotic plaques, TRAF-3 expression is upregulated in areas with high shear stress. Overexpression of TRAF-3 inhibits endothelial expression of proinflammatory cytokines and tissue factor and blocks DNA-binding activity of the transcription factor AP-1; it thereby prevents CD40-induced endothelial activation. Thus, upregulation of TRAF-3 represents a novel mechanism for preserving the functional integrity of the endothelial monolayer.

Original languageEnglish (US)
Pages (from-to)1451-1458
Number of pages8
JournalJournal of Clinical Investigation
Volume108
Issue number10
DOIs
StatePublished - 2001
Externally publishedYes

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TNF Receptor-Associated Factor 3
Up-Regulation
Endothelial Cells
Atherosclerosis
CD40 Ligand
Transcription Factor AP-1
Thromboplastin
Atherosclerotic Plaques
Endothelium
Cultured Cells
Arteries
Cytokines
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. / Urbich, Carmen; Mallat, Ziad; Tedgui, Alain; Clauss, Matthias; Zeiher, Andreas M.; Dimmeler, Stefanie.

In: Journal of Clinical Investigation, Vol. 108, No. 10, 2001, p. 1451-1458.

Research output: Contribution to journalArticle

Urbich, Carmen ; Mallat, Ziad ; Tedgui, Alain ; Clauss, Matthias ; Zeiher, Andreas M. ; Dimmeler, Stefanie. / Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. In: Journal of Clinical Investigation. 2001 ; Vol. 108, No. 10. pp. 1451-1458.
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AU - Dimmeler, Stefanie

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