Abstract 16794: COX-2 and Cardiovascular Risk; Identification of New COX-2 Targets and Pathways Outside the Vessel Wall
COX-2 is the therapeutic target of anti-inflammatory drugs and also plays a role in cancer, but use of selective COX-2 inhibitors (e.g. rofecoxib) or non-selective COX-1/COX-2 inhibitors (e.g. ibuprofen) is associated with increased cardiovascular events. This is thought to be due to loss of COX-2-dependent prostacyclin in the vessel but this hypothesis is based on indirect evidence from urinary metabolites. We have recently shown that systemic vascular prostacyclin is driven by COX-1 and that urinary metabolites do not reflect circulating levels (Kirkby et al. PNAS. 2012). We are now left with no clear explanation of COX-2 protects the cardiovascular system. Here we have used an ApoE-/- mouse model to confirm that COX-2 limits atherosclerosis, despite playing no role in local vascular prostacyclin release. In order to find new mechanisms we performed microarray analysis of key tissues that participate in atherosclerosis: liver, lung and thymus (Figure A). We made two important observations. Firstly, we found consistent alterations in lymphocyte gene pathways. In agreement, ApoE-/-/COX-2-/- mice had increased levels of circulating lymphocytes and associated cytokines (IL-2 and IL-12), and an increase in T-lymphocytes in atherosclerotic plaques (Figure B). Secondly, we found the most altered gene in all tissues was the relatively unknown candidate, ral guanine nucleotide dissociation stimulator-like 1 (rgl1). Down regulation of rgl1 was confirmed by qPCR, and pilot experiments show it to be co-induced with COX-2 in mice, in vivo and in human cells, in vitro. We suggest that it is now critical to investigate how COX-2 regulates genes and pathways out side the vessel in order to truly understand how COX-2 drugs cause cardiovascular side effects. In this way we can reopen the area for development of new treatments for inflammation and cancer.
Figure: Altered gene transcripts in tissues from ApoE-/-COX-2-/- mice (A) and plaque T-lymphocyte content (B)
- © 2013 by American Heart Association, Inc.