title: Dimethylarginine dimethylaminohydrolase 2 regulates nitric oxide synthesis and hemodynamics and determines outcome in polymicrobial sepsis.
abstract: OBJECTIVE
  Nitric oxide is a key to numerous physiological and pathophysiological processes. Nitric oxide production is regulated endogenously by 2 methylarginines, asymmetric dimethylarginine (ADMA) and monomethyl-L-arginine. The enzyme that specifically metabolizes asymmetric dimethylarginine and monomethyl-L-arginine is dimethylarginine dimethylaminohydrolase (DDAH). The first isoform dimethylarginine dimethylaminohydrolase 1 has previously been shown to be an important regulator of methylarginines in both health and disease. This study explores for the first time the role of endogenous dimethylarginine dimethylaminohydrolase 2 in regulating cardiovascular physiology and also determines the functional impact of dimethylarginine dimethylaminohydrolase 2 deletion on outcome and immune function in sepsis.
  
  
  RESULTS
  Mice, globally deficient in Ddah2, were compared with their wild-type littermates to determine the physiological role of Ddah2 using in vivo and ex vivo assessments of vascular function. We show that global knockout of Ddah2 results in elevated blood pressure during periods of activity (mean [SEM], 118.5 [1.3] versus 112.7 [1.1] mm Hg; P=0.025) and changes in vascular responsiveness mediated by changes in methylarginine concentration, mean myocardial tissue asymmetric dimethylarginine (SEM) was 0.89 (0.06) versus 0.67 (0.05) μmol/L (P=0.02) and systemic nitric oxide concentrations. In a model of severe polymicrobial sepsis, Ddah2 knockout affects outcome (120-hour survival was 12% in Ddah2 knockouts versus 53% in wild-type animals; P<0.001). Monocyte-specific deletion of Ddah2 results in a similar pattern of increased severity to that seen in globally deficient animals.
  
  
  CONCLUSIONS
  Ddah2 has a regulatory role both in normal physiology and in determining outcome of severe polymicrobial sepsis. Elucidation of this role identifies a mechanism for the observed relationship between Ddah2 polymorphisms, cardiovascular disease, and outcome in sepsis.
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Simon
authors: S
authors: Lambden
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Peter
authors: P
authors: Kelly
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Blerina
authors: B
authors: Ahmetaj-Shala
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Zhen
authors: Z
authors: Wang
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Benjamin
authors: B
authors: Lee
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Manasi
authors: M
authors: Nandi
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Belen
authors: B
authors: Torondel
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Matthew
authors: M
authors: Delahaye
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Laura
authors: L
authors: Dowsett
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Sophie
authors: S
authors: Piper
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: James
authors: J
authors: Tomlinson
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Ben
authors: B
authors: Caplin
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Lucy
authors: L
authors: Colman
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Olga
authors: O
authors: Boruc
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Anna
authors: A
authors: Slaviero
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Lan
authors: L
authors: Zhao
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Eduardo
authors: E
authors: Oliver
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Sanjay
authors: S
authors: Khadayate
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Mervyn
authors: M
authors: Singer
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.).
authors: Francesca
authors: F
authors: Arrigoni
authors: From the Nitric Oxide Signalling Group (S.L., P.K., Z.W., B.L., B.T., M.D., L.D., S.P., J.T., B.C., L.C., O.B., A.S., J.L.) and Bioinformatics Core (S.K.), Clinical Sciences Centre, Medical Research Council, Hammersmith Hospital, London, United Kingdom; National Heart and Lung Institute (B.A.-S.) and Centre for Pharmacology and Therapeutics (L.Z., E.O.), Imperial College London, London, United Kingdom; Institute of Pharmaceutical Science, King's College London, London, United Kingdom (M.N.); Bloomsbury Institute of Intensive Care Medicine, Division of Medicine, University College London, London, United Kingdom (M.S.); and School of Pharmacy and Chemistry, Kingston University, Surrey, United Kingdom (F.A.). james.leiper@csc.mrc.ac.uk.
authors: James
authors: J
authors: Leiper
mesh_terms: D000581:Amidohydrolases / Q000378:metabolism*; D000818:Animals; D058491:Bacterial Load; D001794:Blood Pressure; D004195:Disease Models, Animal; D006439:Hemodynamics; D017737:Macrophages, Peritoneal / Q000378:metabolism; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000096:biosynthesis*; D011379:Prognosis; D018805:Sepsis / Q000378:metabolism / Q000382:microbiology / Q000503:physiopathology*; D017423:Sequence Analysis, RNA; D013686:Telemetry
chemical_list: D009569:Nitric Oxide; D000581:Amidohydrolases; C059999:dimethylargininase
keywords: N,N-dimethylarginine; dimethylarginine dimethylaminohydrolase 2; hypertension; nitric oxide; sepsis