Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH 2 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-α–induced TF expression and activity in human aortic endothelial cells. Celecoxib (10 −5 mol/L) reduced activation of c-jun terminal NH 2 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-α–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.