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

Cardiovasc Res. 2020 Oct 1;116(12):1972-1980. doi: 10.1093/cvr/cvz290.


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.

Keywords: PGE2; ADMA; COX-2; Methylarginines; Non-steroidal anti-inflammatory drugs; Prostacyclin; Vioxx.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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
  • Mice, Knockout
  • 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


  • Cyclooxygenase 2 Inhibitors
  • PPAR-beta
  • Ppard protein, mouse
  • Prostaglandins I
  • Ptgir protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Epoprostenol
  • Receptors, Prostaglandin E
  • N,N-dimethylarginine
  • Cytochrome P-450 Enzyme System
  • Arginine
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Intramolecular Oxidoreductases
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • prostacyclin synthetase