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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.

SUBMITTER: Kirkby NS 

PROVIDER: S-EPMC4041570 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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

Kirkby Nicholas S NS   Lundberg Martina H MH   Wright William R WR   Warner Timothy D TD   Paul-Clark Mark J MJ   Mitchell Jane A JA  

PloS one 20140602 6


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.  ...[more]

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