thromboplastin and rofecoxib

In endothelial cells (EC), celecoxib inhibits expression of tissue factor (TF), a key protein for initiation and propagation of thrombus formation. The current study was designed to examine the effect of celecoxib on TF expression and activity in VSMC. In contrast to EC, celecoxib increased TNF-alpha-induced TF expression and surface activity in VSMC by 33% and 20%, respectively, as compared to TNF-alpha alone, while rofecoxib or NS-398 had no effect. Celecoxib increased p38 MAP kinase (p38), p44/42 MAP kinase (ERK), and p70S6 kinase (p70S6K) phosphorylation while leaving JNK activation unaffected. Simultaneous inhibition of p38 and ERK reduced TNF-alpha-induced TF expression by 59%, while inhibition of JNK with SP600125 did not affect TF expression. Thus, in contrast to endothelial cells, celecoxib does not inhibit TF expression in VSMC, but instead enhances it. As neither rofecoxib nor NS-398 affected TF expression, this effect does not seem to be related to COX-2 inhibition but rather appears to be mediated by an increase in p38, ERK, and p70S6K activation. The observation that the inhibiting effect of celecoxib on endothelial TF expression does not extend to VSMC may have important implications for patients with cardiovascular disease.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Atherosclerosis; Celecoxib; Cell Line; Endothelium, Vascular; Gene Expression Regulation; Heart Diseases; Humans; Lactones; Muscle, Smooth, Vascular; Pyrazoles; Sulfonamides; Sulfones; Thromboplastin; Thrombosis; Transcription, Genetic; Tumor Necrosis Factor-alpha

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.. 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.. 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.

Topics: Aorta; Celecoxib; Cells, Cultured; Cyclooxygenase Inhibitors; Endothelium, Vascular; Humans; JNK Mitogen-Activated Protein Kinases; Lactones; Mitogen-Activated Protein Kinases; Phosphorylation; Pyrazoles; Signal Transduction; Sulfonamides; Sulfones; Thromboplastin; Tumor Necrosis Factor-alpha