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J. Biol. Chem., Vol. 281, Issue 17, 11792-11804, April 28, 2006

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Cyclooxygenase-2 Induction and Prostacyclin Release by Protease-activated Receptors in Endothelial Cells Require Cooperation between Mitogen-activated Protein Kinase and NF-B Pathways^*

Farisa Syeda, Jennifer Grosjean, Rebecca A. Houliston, Rosemary J. Keogh, Tom D. Carter^¶, Ewa Paleolog, and Caroline P. D. Wheeler-Jones¹

From the Department of Veterinary Basic Sciences, Royal Veterinary College, Royal College Street, London NW1 0TU, United Kingdom, Kennedy Institute of Rheumatology and Division of Surgery, Oncology, Reproductive Biology, and Anaesthetics, Faculty of Medicine, Imperial College, London W6 8LH, United Kingdom, and ^¶National Institute for Medical Research, Mill Hill, London NW7 1AA, United Kingdom

The functional significance of protease-activated receptors (PARs) in endothelial cells is largely undefined, and the intracellular consequences of their activation are poorly understood. Here, we show that the serine protease thrombin, a PAR-1-selective peptide (TFLLRN), and SLIGKV (PAR-2-selective peptide) induce cyclooxygenase-2 (COX-2) protein and mRNA expression in human endothelial cells without modifying COX-1 expression. COX-2 induction was accompanied by sustained production of 6-keto-PGF₁, the stable hydrolysis product of prostacyclin, and this was inhibited by indomethacin and the COX-2-selective inhibitor NS398. PAR-1 and PAR-2 stimulation rapidly activated both ERK1/2 and p38^MAPK, and pharmacological blockade of MEK with either PD98059 or U0126 or of p38^MAPK by SB203580 or SB202190 strongly inhibited thrombin- and SLIGKV-induced COX-2 expression and 6-keto-PGF₁ formation. Thrombin and peptide agonists of PAR-1 and PAR-2 increased luciferase activity in human umbilical vein endothelial cells infected with an NF-B-dependent luciferase reporter adenovirus, and this, as well as PAR-induced 6-keto-PGF₁ synthesis, was inhibited by co-infection with adenovirus encoding wild-type or mutated (Y42F) IB. Thrombin- and SLIGKV-induced COX-2 expression and 6-keto-PGF₁ generation were markedly attenuated by the NF-B inhibitor PG490 and partially inhibited by the proteasome pathway inhibitor MG-132. Activation of PAR-1 or PAR-2 promoted nuclear translocation and phosphorylation of p65-NF-B, and thrombin-induced but not PAR-2-induced p65-NF-B phosphorylation was reduced by inhibition of MEK or p38^MAPK. Activation of PAR-4 by AYPGKF increased phosphorylation of ERK1/2 and p38^MAPK without modifying NF-B activation or COX-2 induction. Our data show that PAR-1 and PAR-2, but not PAR-4, are coupled with COX-2 expression and sustained endothelial production of vasculoprotective prostacyclin by mechanisms that depend on ERK1/2, p38^MAPK, and IB-dependent NF-B activation.

Received for publication, August 23, 2005 , and in revised form, February 7, 2006.

^* This work was supported by the British Heart Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Veterinary Basic Sciences, Royal Veterinary College, Royal College St., London NW1 0TU, UK. Tel.: 44-0207-468-5237; Fax: 44-0207-468-5204; E-mail: cwheeler{at}rvc.ac.uk.

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