The Journal of Experimental Medicine
Avanti Polar Lipids
  Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents
Published online August 27, 2007
doi:10.1084/jem.20070828
The Journal of Experimental Medicine, Vol. 204, No. 9, 2053-2061
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Ghosh et al.
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental Material Index
Right arrow Alert me when this article is cited
Right arrow Citation Map
Services
Right arrow Email this article
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new content in the JEM
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via CrossRef
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Ghosh, M.
Right arrow Articles by Hla, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Ghosh, M.
Right arrow Articles by Hla, T.
Related Collections
Right arrowRelated Article
Social Bookmarking
Add to CiteULike   Add to Complore   Add to Connotea   Add to Del.icio.us   Add to Digg   Add to Reddit   Add to Technorati  
What's this?

BRIEF DEFINITIVE REPORT

 COX-2 suppresses tissue factor expression via endocannabinoid-directed PPAR{delta} activation

Mallika Ghosh1, Haibin Wang2,3,4, Youxi Ai1, Elisa Romeo5, James P. Luyendyk5, Jeffrey M. Peters6,7, Nigel Mackman5, Sudhansu K. Dey2,3,4, and Timothy Hla1

1 Center for Vascular Biology, Department of Cell Biology, University of Connecticut Health Center, Farmington, CT 06030
2 Departments of Pediatrics, 3 Cell and Developmental Biology, and 4 Pharmacology, Division of Reproductive and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN 37232
5 Department of Immunology, Scripps Research Institute, La Jolla, CA 92037
6 Department of Veterinary Science and 7 Center for Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, PA 16802

CORRESPONDENCE Timothy Hla: hla{at}nso2.uchc.edu

Although cyclooxygenase (COX)-2 inhibitors (coxibs) are effective in controlling inflammation, pain, and tumorigenesis, their use is limited by the recent revelation of increased adverse cardiovascular events. The mechanistic basis of this side effect is not well understood. We show that the metabolism of endocannabinoids by the endothelial cell COX-2 coupled to the prostacyclin (PGI2) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator–activated receptor (PPAR) {delta}, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPAR{delta} activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPAR{delta} agonists suppress coxib-induced TF expression and decrease circulating TF activity. We provide evidence that COX-2–dependent attenuation of TF expression is abrogated by coxibs, which may explain the prothrombotic side-effects for this class of drugs. Furthermore, PPAR{delta} agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects.

Abbreviations used: AA, arachidonic acid; AEA, anandamide; AG, arachidonyl glycerol; COX, cyclooxygenase; EC, endothelial cell; HUVEC, human umbilical vein EC; NE, noladin ether; PGFS, PGF2{alpha} synthase; PGI2, prostacyclin; PGIS, PGI2 synthase; PPAR, peroxisomal proliferator–activated receptor; PPP, platelet poor plasma; q, quantitative; TF, tissue factor; VSA, valeryl salicylate.


Add to CiteULike CiteULike   Add to Complore Complore   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Digg Digg   Add to Reddit Reddit   Add to Technorati Technorati    What's this?

Related Article

Following the trail from COX-2 to clotting
Hema Bashyam
J. Exp. Med. 2007 204: 2011. [Full Text] [PDF]



This article has been cited by other articles:



  Home | Help | Feedback | Subscriptions | Archive | Search
TABLE OF CONTENTS