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COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation
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 metabol...
Autores principales: | , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2007
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118704/ https://www.ncbi.nlm.nih.gov/pubmed/17724132 http://dx.doi.org/10.1084/jem.20070828 |
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author | Ghosh, Mallika Wang, Haibin Ai, Youxi Romeo, Elisa Luyendyk, James P. Peters, Jeffrey M. Mackman, Nigel Dey, Sudhansu K. Hla, Timothy |
author_facet | Ghosh, Mallika Wang, Haibin Ai, Youxi Romeo, Elisa Luyendyk, James P. Peters, Jeffrey M. Mackman, Nigel Dey, Sudhansu K. Hla, Timothy |
author_sort | Ghosh, Mallika |
collection | PubMed |
description | 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 (PGI(2)) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator–activated receptor (PPAR) δ, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARδ activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARδ 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, PPARδ agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects. |
format | Text |
id | pubmed-2118704 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2007 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-21187042008-03-03 COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation Ghosh, Mallika Wang, Haibin Ai, Youxi Romeo, Elisa Luyendyk, James P. Peters, Jeffrey M. Mackman, Nigel Dey, Sudhansu K. Hla, Timothy J Exp Med Brief Definitive Reports 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 (PGI(2)) synthase (PGIS) activates the nuclear receptor peroxisomal proliferator–activated receptor (PPAR) δ, which negatively regulates the expression of tissue factor (TF), the primary initiator of blood coagulation. Coxibs suppress PPARδ activity and induce TF expression in vascular endothelium and elevate circulating TF activity in vivo. Importantly, PPARδ 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, PPARδ agonists may be used therapeutically to suppress coxib-induced cardiovascular side effects. The Rockefeller University Press 2007-09-03 /pmc/articles/PMC2118704/ /pubmed/17724132 http://dx.doi.org/10.1084/jem.20070828 Text en Copyright © 2007, The Rockefeller University Press This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Brief Definitive Reports Ghosh, Mallika Wang, Haibin Ai, Youxi Romeo, Elisa Luyendyk, James P. Peters, Jeffrey M. Mackman, Nigel Dey, Sudhansu K. Hla, Timothy COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title | COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title_full | COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title_fullStr | COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title_full_unstemmed | COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title_short | COX-2 suppresses tissue factor expression via endocannabinoid-directed PPARδ activation |
title_sort | cox-2 suppresses tissue factor expression via endocannabinoid-directed pparδ activation |
topic | Brief Definitive Reports |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118704/ https://www.ncbi.nlm.nih.gov/pubmed/17724132 http://dx.doi.org/10.1084/jem.20070828 |
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