Differential effect of celecoxib on tissue factor expression in human endothelial and vascular smooth muscle cells.
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.
Steffel
Jan
J
Cardiovascular Research, Physiology Institute, University of Zürich, Zürich, Switzerland.
Akhmedov
Alexander
A
Fähndrich
Carine
C
Ruschitzka
Frank
F
Lüscher
Thomas F
TF
Tanner
Felix C
FC
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D050197:Atherosclerosis / Q000473:pathology; D000068579:Celecoxib; D002460:Cell Line; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation; D006331:Heart Diseases / Q000473:pathology; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology*; D013450:Sulfones / Q000494:pharmacology; D013925:Thromboplastin / Q000096:biosynthesis*; D013927:Thrombosis / Q000473:pathology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007783:Lactones; D011720:Pyrazoles; D013449:Sulfonamides; D013450:Sulfones; D014409:Tumor Necrosis Factor-alpha; C116926:rofecoxib; D013925:Thromboplastin; D000068579:Celecoxib