title: COX-2 protects against atherosclerosis independently of local vascular prostacyclin: identification of COX-2 associated pathways implicate Rgl1 and lymphocyte networks.
abstract: Cyxlo-oxygenase (COX)-2 inhibitors, including traditional nonsteroidal anti-inflammatory drugs (NSAIDs) are associated with increased cardiovascular side effects, including myocardial infarction. We and others have shown that COX-1 and not COX-2 drives vascular prostacyclin in the healthy cardiovascular system, re-opening the question of how COX-2 might regulate cardiovascular health. In diseased, atherosclerotic vessels, the relative contribution of COX-2 to prostacyclin formation is not clear. Here we have used apoE(-/-)/COX-2(-/-) mice to show that, whilst COX-2 profoundly limits atherosclerosis, this protection is independent of local prostacyclin release. These data further illustrate the need to look for new explanations, targets and pathways to define the COX/NSAID/cardiovascular risk axis. Gene expression profiles in tissues from apoE(-/-)/COX-2(-/-) mice showed increased lymphocyte pathways that were validated by showing increased T-lymphocytes in plaques and elevated plasma Th1-type cytokines. In addition, we identified a novel target gene, rgl1, whose expression was strongly reduced by COX-2 deletion across all examined tissues. This study is the first to demonstrate that COX-2 protects vessels against atherosclerotic lesions independently of local vascular prostacyclin and uses systems biology approaches to identify new mechanisms relevant to development of next generation NSAIDs.
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, United Kingdom; The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, United Kingdom; The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Martina H
authors.initials: MH
authors.lastname: Lundberg
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: William R
authors.initials: WR
authors.lastname: Wright
authors.affiliation: The William Harvey Research Institute, Barts & the London School of Medicine & Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Paul-Clark
authors.affiliation: National Heart & Lung Institute, Imperial College London, London, United Kingdom.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology; D001808:Blood Vessels / Q000378:metabolism* / Q000473:pathology; D051546:Cyclooxygenase 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011464:Epoprostenol / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D015971:Gene Expression Regulation, Enzymologic; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000378:metabolism*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism*; D059467:Transcriptome / Q000235:genetics; D015854:Up-Regulation / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; D020662:Guanine Nucleotide Exchange Factors; D020011:Protective Agents; C097104:Rgl1 protein, mouse; D011464:Epoprostenol; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2