Simon Lambden1, Peter Kelly1, Blerina Ahmetaj-Shala1, Zhen Wang1, Benjamin Lee1, Manasi Nandi1, Belen Torondel1, Matthew Delahaye1, Laura Dowsett1, Sophie Piper1, James Tomlinson1, Ben Caplin1, Lucy Colman1, Olga Boruc1, Anna Slaviero1, Lan Zhao1, Eduardo Oliver1, Sanjay Khadayate1, Mervyn Singer1, Francesca Arrigoni1, James Leiper2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Christina Nelson; Jameisha Lee; Kang Ko; Andrew G Sikora; Mark D Bonnen; Perenlei Enkhbaatar; Yohannes T Ghebre Journal: Front Pharmacol Date: 2017-01-26 Impact factor: 5.810
Authors: Martin Sebastian Winkler; Stefan Kluge; Maximilian Holzmann; Eileen Moritz; Linda Robbe; Antonia Bauer; Corinne Zahrte; Marion Priefler; Edzard Schwedhelm; Rainer H Böger; Alwin E Goetz; Axel Nierhaus; Christian Zoellner Journal: Crit Care Date: 2017-07-15 Impact factor: 9.097
Authors: Clemens Lange; Freya Mowat; Haroon Sayed; Manjit Mehad; Lucie Duluc; Sophie Piper; Ulrich Luhmann; Manasi Nandi; Peter Kelly; Alexander Smith; Robin Ali; James Leiper; James Bainbridge Journal: Exp Eye Res Date: 2016-05-12 Impact factor: 3.467