Published Online
on March 28, 2005

A more recent version of this article appeared on April 5, 2005

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Submitted on September 30, 2004
Revised on December 9, 2004
Accepted on December 23, 2004

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, and 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.

^* To whom correspondence should be addressed. E-mail: felix.tanner{at}access.unizh.ch.

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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