COX-2 protects against atherosclerosis independently of local vascular prostacyclin: identification of COX-2 associated pathways implicate Rgl1 and lymphocyte networks

• Published in: PloS one 2014-06, Vol.9 (6), p.e98165
• Main Authors: Kirkby, Nicholas S, Lundberg, Martina H, Wright, William R, Warner, Timothy D, Paul-Clark, Mark J, Mitchell, Jane A
• Format: Article
• Language: English
• Subjects: Animal tissues; Animals; Anti-inflammatory agents; Apolipoprotein E; Apolipoproteins; Apolipoproteins E - deficiency; Apolipoproteins E - metabolism; Arteriosclerosis; Arthritis; Atherosclerosis; Atherosclerosis - enzymology; Atherosclerosis - pathology; Biology and Life Sciences; Blood vessels; Blood Vessels - metabolism; Blood Vessels - pathology; Cancer; Cardiovascular diseases; Cardiovascular system; Cholesterol; COX-2 inhibitors; Cyclooxygenase 2 - deficiency; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Cyclooxygenase-1; Cyclooxygenase-2; Cytokines; Dentistry; Epoprostenol - metabolism; Female; Gene Deletion; Gene expression; Gene Expression Regulation, Enzymologic; Guanine Nucleotide Exchange Factors - metabolism; Health risks; Heart; Heart attack; Inflammation; Lesions; Lymphocytes; Lymphocytes T; Male; Medicine and Health Sciences; Metabolites; Mice; Mice, Inbred C57BL; Myocardial infarction; Nonsteroidal anti-inflammatory drugs; Oxygenase; Plaques; Prostacyclin; Protective Agents - metabolism; Side effects; Signal Transduction; Studies; T-Lymphocytes - metabolism; Thrombosis; Transcriptome - genetics; Up-Regulation - genetics
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0098165

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.