Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis.

Cardiovascular research 2020 Oct 01

filter terms:

Cardiovascular side effects caused by non-steroidal anti-inflammatory drugs (NSAIDs), which all inhibit cyclooxygenase (COX)-2, have prevented development of new drugs that target prostaglandins to treat inflammation and cancer. Microsomal prostaglandin E synthase-1 (mPGES-1) inhibitors have efficacy in the NSAID arena but their cardiovascular safety is not known. Our previous work identified asymmetric dimethylarginine (ADMA), an inhibitor of endothelial nitric oxide synthase, as a potential biomarker of cardiovascular toxicity associated with blockade of COX-2. Here, we have used pharmacological tools and genetically modified mice to delineate mPGES-1 and COX-2 in the regulation of ADMA. Inhibition of COX-2 but not mPGES-1 deletion resulted in increased plasma ADMA levels. mPGES-1 deletion but not COX-2 inhibition resulted in increased plasma prostacyclin levels. These differences were explained by distinct compartmentalization of COX-2 and mPGES-1 in the kidney. Data from prostanoid synthase/receptor knockout mice showed that the COX-2/ADMA axis is controlled by prostacyclin receptors (IP and PPARβ/δ) and the inhibitory PGE2 receptor EP4, but not other PGE2 receptors. These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA. © The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Citation

Nicholas S Kirkby, Joan Raouf, Blerina Ahmetaj-Shala, Bin Liu, Sarah I Mazi, Matthew L Edin, Mark Geoffrey Chambers, Marina Korotkova, Xiaomeng Wang, Walter Wahli, Darryl C Zeldin, Rolf Nüsing, Yingbi Zhou, Per-Johan Jakobsson, Jane A Mitchell. Mechanistic definition of the cardiovascular mPGES-1/COX-2/ADMA axis. Cardiovascular research. 2020 Oct 01;116(12):1972-1980