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

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

Author information

1
From the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.).
2
From the Cardiothoracic Pharmacology, Vascular Biology, National Heart and Lung Institute, Imperial College, London, United Kingdom (B.A.-S., N.S.K., M.Al'Y., S.M., J.A.M.); The William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary, University of London, London, United Kingdom (R.K., A.T.T., P.C.J.A., T.D.W.); King Fahad Cardiac Center of King Saud University, Riyadh, Saudi Arabia (M.Al'Y., S.M.,); MRC Clinical Sciences, Imperial College London, Nitric Oxide Signalling Group, Hammersmith Hospital, DuCane Road, London, United Kingdom (Z.W., J.A.P.T., J.L.); School of Life and Medical Sciences, University of Hertfordshire, College Lane, Hatfield, United Kingdom (L.M.); and Institute of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, Frankfurt, Germany (R.M.N.). j.a.mitchell@ic.ac.uk.

Abstract

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

PMID:
25492024
PMCID:
PMC4768634
DOI:
10.1161/CIRCULATIONAHA.114.011591
[Indexed for MEDLINE]
Free PMC Article

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