title: Evidence that links loss of cyclooxygenase-2 with increased asymmetric dimethylarginine: novel explanation of cardiovascular side effects associated with anti-inflammatory drugs.
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.
  
  
  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.
authors.affiliation: 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.).
authors.forename: Blerina
authors.initials: B
authors.lastname: Ahmetaj-Shala
authors.affiliation: 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.).
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Kirkby
authors.affiliation: 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.).
authors.forename: Rebecca
authors.initials: R
authors.lastname: Knowles
authors.affiliation: 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.).
authors.forename: Malak
authors.initials: M
authors.lastname: Al'Yamani
authors.affiliation: 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.).
authors.forename: Sarah
authors.initials: S
authors.lastname: Mazi
authors.affiliation: 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.).
authors.forename: Zhen
authors.initials: Z
authors.lastname: Wang
authors.affiliation: 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.).
authors.forename: Arthur T
authors.initials: AT
authors.lastname: Tucker
authors.affiliation: 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.).
authors.forename: Louise
authors.initials: L
authors.lastname: Mackenzie
authors.affiliation: 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.).
authors.forename: Paul C J
authors.initials: PC
authors.lastname: Armstrong
authors.affiliation: 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.).
authors.forename: Rolf M
authors.initials: RM
authors.lastname: Nüsing
authors.affiliation: 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.).
authors.forename: James A P
authors.initials: JA
authors.lastname: Tomlinson
authors.affiliation: 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.).
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Warner
authors.affiliation: 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.).
authors.forename: James
authors.initials: J
authors.lastname: Leiper
authors.affiliation: 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.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Mitchell
mesh_terms: D000328:Adult; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000188:drug therapy; D051546:Cyclooxygenase 2 / Q000172:deficiency*; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D055815:Young Adult
chemical_list: D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D052246:Cyclooxygenase 2 Inhibitors; C018524:N,N-dimethylarginine; D001120:Arginine; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2
keywords: endothelium; kidney; nitric oxide; pharmacology; prostaglandins