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Celecoxib decreases endothelial tissue factor expression through inhibition of c-Jun terminal NH2 kinase

Jan Steffel1, Matthias Hermann, Helen Greutert

  • 1Cardiovascular Research, Physiology Institute, University of Zurich, Switzerland.

Circulation
|March 30, 2005
PubMed
Abstract

Insights

Celecoxib, unlike other coxibs, reduces tissue factor (TF) expression in human aortic cells by inhibiting JNK. This suggests distinct drug effects relevant for cardiovascular disease patients.

Area of Science:

  • Cardiovascular Pharmacology
  • Molecular Biology
  • Thrombosis Research

Background:

  • Selective cyclooxygenase-2 inhibitors (coxibs) may increase thrombotic risk in cardiovascular patients.
  • Tissue factor (TF) is implicated in atherosclerosis and thrombosis pathogenesis.
  • Investigating coxibs' effects on TF expression is crucial for patient safety.

Purpose of the Study:

  • To examine the differential effects of various coxibs on tissue factor (TF) expression.
  • To elucidate the molecular mechanisms underlying coxib-mediated changes in TF expression.
  • To assess the clinical relevance of these findings for patients with atherosclerotic vascular diseases.

Main Methods:

  • Human aortic endothelial cells were treated with different coxibs (celecoxib, rofecoxib, NS-398).
  • Tumor necrosis factor-alpha (TNF-α) was used to induce TF expression and activity.
  • Western blotting and specific inhibitors (SP600125) were employed to analyze signaling pathways, including JNK, p38 MAPK, and p44/42 MAPK.

Main Results:

  • Celecoxib significantly decreased TNF-α-induced TF expression and activity.
  • Rofecoxib and NS-398 did not affect TF expression or activity.
  • Celecoxib inhibited JNK phosphorylation, a mechanism confirmed by SP600125, while other coxibs did not.
  • Celecoxib's effect on TF was independent of COX-2 inhibition.

Conclusions:

  • Celecoxib exhibits a unique ability to reduce TF expression and activity in endothelial cells.
  • This effect is mediated by the inhibition of JNK phosphorylation, not COX-2 inhibition.
  • Significant heterogeneity exists among coxibs regarding their impact on TF, with potential clinical implications for cardiovascular and atherosclerotic diseases.

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