Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs

Circulation. 2015 Feb 17;131(7):633-42. doi: 10.1161/CIRCULATIONAHA.114.011591. Epub 2014 Dec 9.


Background: Cardiovascular side effects associated with cyclooxygenase-2 inhibitor drugs dominate clinical concern. Cyclooxygenase-2 is expressed in the renal medulla where inhibition causes fluid retention and increased blood pressure. However, the mechanisms linking cyclooxygenase-2 inhibition and cardiovascular events are unknown and no biomarkers have been identified.

Methods and results: Transcriptome analysis of wild-type and cyclooxygenase-2(-/-) mouse tissues revealed 1 gene altered in the heart and aorta, but >1000 genes altered in the renal medulla, including those regulating the endogenous nitric oxide synthase inhibitors asymmetrical dimethylarginine (ADMA) and monomethyl-l-arginine. Cyclo-oxygenase-2(-/-) mice had increased plasma levels of ADMA and monomethyl-l-arginine and reduced endothelial nitric oxide responses. These genes and methylarginines were not similarly altered in mice lacking prostacyclin receptors. Wild-type mice or human volunteers taking cyclooxygenase-2 inhibitors also showed increased plasma ADMA. Endothelial nitric oxide is cardio-protective, reducing thrombosis and atherosclerosis. Consequently, increased ADMA is associated with cardiovascular disease. Thus, our study identifies ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction with nonsteroidal anti-inflammatory drug usage.

Conclusions: We identify the endogenous endothelial nitric oxide synthase inhibitor ADMA as a biomarker and mechanistic bridge between renal cyclooxygenase-2 inhibition and systemic vascular dysfunction.

Keywords: endothelium; kidney; nitric oxide; pharmacology; prostaglandins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Anti-Inflammatory Agents / adverse effects*
  • Arginine / analogs & derivatives*
  • Arginine / blood
  • Biomarkers / blood
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / drug therapy
  • Cyclooxygenase 2 / deficiency*
  • Cyclooxygenase 2 Inhibitors / adverse effects*
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organ Culture Techniques
  • Young Adult


  • Anti-Inflammatory Agents
  • Biomarkers
  • Cyclooxygenase 2 Inhibitors
  • N,N-dimethylarginine
  • Arginine
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2