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

Abstract

BACKGROUND:

Despite potential antiinflammatory properties, the use of selective cyclooxygenase-2 inhibitors (coxibs) in patients with cardiovascular diseases has been questioned because of a possibly increased thrombotic risk. Tissue factor (TF), a key protein for initiation of coagulation, has been implicated in the pathogenesis of atherosclerosis and thrombosis. Hence, we examined the effect of different coxibs on TF expression.

METHODS AND RESULTS:

Celecoxib (10(-5) mol/L), but not rofecoxib (10(-7) to 10(-5) mol/L) or the experimental coxib NS-398 (10(-7) to 10(-5) mol/L), decreased tumor necrosis factor-alpha-induced TF expression and activity in human aortic endothelial cells. Celecoxib (10(-5) mol/L) reduced activation of c-jun terminal NH2 kinase (JNK), whereas it did not affect p38 mitogen-activated protein (MAP) kinase or p44/42 MAP kinase; in contrast, JNK activation was not affected by rofecoxib (10(-5) mol/L) or NS-398 (10(-5) mol/L). TF expression was reduced in a concentration-dependent manner by pretreatment with SP600125 (10(-7) to 10(-6) mol/L), a specific inhibitor of JNK, which confirms that JNK regulates tumor necrosis factor-alpha-induced TF expression.

CONCLUSIONS:

Celecoxib reduced TF expression and activity in human aortic endothelial cells. Because neither rofecoxib nor the experimental coxib NS-398 affected TF expression, this effect occurs independently of COX-2 inhibition; it is rather mediated through inhibition of JNK phosphorylation. These data indicate a distinct heterogeneity within this class of drugs, which may be clinically relevant, especially for patients with atherosclerotic vascular diseases.

• Authors: Jan Steffel, Matthias Hermann, Helen Greutert, Steffen Gay, Thomas F Lüscher, Frank Ruschitzka, Felix C Tanner
• Journal: Circulation (Circulation) Vol. 111 Issue 13 Pg. 1685-9 (Apr 05 2005) ISSN: 1524-4539 [Electronic] United States
• PMID: 15795326 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cyclooxygenase Inhibitors
• Lactones
• Pyrazoles
• Sulfonamides
• Sulfones
• Tumor Necrosis Factor-alpha
• rofecoxib
• Thromboplastin
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinases
• Celecoxib

Topics

• Aorta (cytology)
• Celecoxib
• Cells, Cultured
• Cyclooxygenase Inhibitors (pharmacology)
• Endothelium, Vascular (metabolism)
• Humans
• JNK Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Lactones (pharmacology)
• Mitogen-Activated Protein Kinases (analysis)
• Phosphorylation (drug effects)
• Pyrazoles (pharmacology)
• Signal Transduction
• Sulfonamides (pharmacology)
• Sulfones (pharmacology)
• Thromboplastin (drug effects, genetics)
• Tumor Necrosis Factor-alpha (pharmacology)