Circulation. 2005;111:1685-1689
Published online before print March 28, 2005,
doi: 10.1161/01.CIR.0000160358.63804.C9
(Circulation. 2005;111:1685-1689.)
© 2005 American Heart Association, Inc.
Celecoxib Decreases Endothelial Tissue Factor Expression Through Inhibition of c-Jun Terminal NH2 Kinase Phosphorylation
Jan Steffel, MD;
Matthias Hermann, MD;
Helen Greutert;
Steffen Gay, MD;
Thomas F. Lüscher, MD;
Frank Ruschitzka, MD*;
Felix C. Tanner, MD*
From Cardiovascular Research (J.S., M.H., H.G., T.F.L., F.C.T.), Physiology Institute, University of Zürich; Cardiology, Cardiovascular Center (J.S., M.H., T.F.L., F.R., F.C.T.) and Center for Experimental Rheumatology (S.G.), University Hospital Zürich, Zürich, Switzerland.
Correspondence to Felix C. Tanner, MD, Cardiovascular Research, Physiology Institute, University of Zurich, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. E-mail felix.tanner{at}access.unizh.ch
Received September 30, 2004; revision received December 9, 2004; accepted December 23, 2004.
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-
–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-–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.
Key Words: atherosclerosis • cardiovascular diseases • coagulation • endothelium • signal transduction
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