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

• Published in: Cardiovascular research Vol. 116; no. 12; pp. 1972 - 1980
• Main Authors: Kirkby, Nicholas S, Raouf, Joan, Ahmetaj-Shala, Blerina, Liu, Bin, Mazi, Sarah I, Edin, Matthew L, Chambers, Mark Geoffrey, Korotkova, Marina, Wang, Xiaomeng, Wahli, Walter, Zeldin, Darryl C, Nüsing, Rolf, Zhou, Yingbi, Jakobsson, Per-Johan, Mitchell, Jane A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01.10.2020
• Subjects: Animals; Aorta - drug effects; Aorta - enzymology; Arginine - analogs & derivatives; Arginine - blood; Cyclooxygenase 2 - metabolism; Cyclooxygenase 2 Inhibitors - pharmacology; Cytochrome P-450 Enzyme System - genetics; Cytochrome P-450 Enzyme System - metabolism; Female; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Kidney - drug effects; Kidney - enzymology; Male; Medicin och hälsovetenskap; Mice, Knockout; Original; PPAR-beta - genetics; PPAR-beta - metabolism; Prostaglandin-E Synthases - antagonists & inhibitors; Prostaglandin-E Synthases - genetics; Prostaglandin-E Synthases - metabolism; Prostaglandins I - blood; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Epoprostenol - genetics; Receptors, Epoprostenol - metabolism; Receptors, Prostaglandin E - genetics; Receptors, Prostaglandin E - metabolism; Vioxx; PGE2; COX-2; ADMA; Prostacyclin; Non-steroidal anti-inflammatory drugs; Methylarginines
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvz290

Abstract Aims 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. Methods and results 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. Conclusion These data demonstrate that inhibition of mPGES-1 spares the renal COX-2/ADMA pathway and define mechanistically how COX-2 regulates ADMA. Graphical Abstract Graphical Abstract