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


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.
Steffel
Jan
J
Cardiovascular Research, Physiology Institute, University of Zurich, Switzerland.
Hermann
Matthias
M
Greutert
Helen
H
Gay
Steffen
S
Lüscher
Thomas F
TF
Ruschitzka
Frank
F
Tanner
Felix C
FC
D001011:Aorta / Q000166:cytology; D000068579:Celecoxib; D002478:Cells, Cultured; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007783:Lactones / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis; D010766:Phosphorylation / Q000187:drug effects; D011720:Pyrazoles / Q000494:pharmacology*; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013925:Thromboplastin / Q000187:drug effects* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016861:Cyclooxygenase Inhibitors; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C116926:rofecoxib; D013925:Thromboplastin; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D000068579:Celecoxib