A Snapshot seminar hosted by the School of Physiology, Pharmacology and Neuroscience
Using specific cyclo-oxygenase-2-deficient mice to understand the pro-thrombotic effects of non-steroidal anti-inflammatory drugs
Introduction: Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen and celecoxib are amongst the most widely used drugs in the world and work by inhibition of COX-2. Regular use of NSAIDs is associated with increased risk of thrombotic events but the mechanisms for this remain unclear with some suggesting it reflects inhibition of cardioprotective COX-2 signalling in either (i) the vascular endothelium or (ii) the kidney, where COX-2 is expressed in interstitial fibroblasts. To address this, we have generated novel cell-specific COX-2 knockout mice targeting each site to determine their contribution to anti-thrombotic protection.
Methods: We generated endothelium-specific (Ptgs2flox/flox;Tie2-Cre) and renal-specific COX-2 knockout models (Ptgs2flox/flox;Fsp1-Cre) using Cre-loxP technology and studied thrombotic response using an in vivo ferric chloride-induced carotid artery injury model. As a control we also generated macrophage-specific COX-2 knockout mice (Ptgs2flox/flox;LysM-Cre) because both Tie2-Cre and Fsp1-Cre drive ‘off-target’ gene deletion in macrophages.
Results: Deletion of COX-2 from either vascular endothelial cells or from the kidney (renal fibroblasts) resulted in an acceleration of thrombotic occlusion after ferric chloride injury to the carotid artery in vivo. This was not accounted for by COX-2 deletion in macrophages.
Conclusions: COX-2 expressed in both the vascular endothelium and renal fibroblasts contribute to systemic anti-thrombotic protection. Although the mechanisms for these effects remains to be determined these data suggest we need to consider both the vasculature and the kidney if we are to understand, treat and predict NSAID-induced cardiovascular risk.