title: Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.
abstract: Inhibition of nitric oxide (NO) signaling may contribute to pathological activation of the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous NO synthase (NOS) inhibitor, and arginine, the NOS substrate. We carried out a community-based case-control study of Gambian children to determine whether ADMA and arginine homeostasis is disrupted during severe or uncomplicated malaria infections. Circulating plasma levels of ADMA and arginine were determined at initial presentation and 28 days later. Plasma ADMA/arginine ratios were elevated in children with acute severe malaria compared to 28-day follow-up values and compared to children with uncomplicated malaria or healthy children (p<0.0001 for each comparison). To test the hypothesis that DDAH1 is inactivated during Plasmodium infection, we examined DDAH1 in a mouse model of severe malaria. Plasmodium berghei ANKA infection inactivated hepatic DDAH1 via a post-transcriptional mechanism as evidenced by stable mRNA transcript number, decreased DDAH1 protein concentration, decreased enzyme activity, elevated tissue ADMA, elevated ADMA/arginine ratio in plasma, and decreased whole blood nitrite concentration. Loss of hepatic DDAH1 activity and disruption of ADMA/arginine homeostasis may contribute to severe malaria pathogenesis by inhibiting NO synthesis.
authors.affiliation: Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Chertow
authors.affiliation: Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America; Radcliffe Department of Medicine, University of Oxford, John Radcliffe Hospital, Headington Oxford, United Kingdom.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Alkaitis
authors.affiliation: Research Technology Branch, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Glenn
authors.initials: G
authors.lastname: Nardone
authors.affiliation: Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Allison K
authors.initials: AK
authors.lastname: Ikeda
authors.affiliation: Section of Paediatrics, Imperial College London, London, United Kingdom.
authors.forename: Aubrey J
authors.initials: AJ
authors.lastname: Cunnington
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Joseph
authors.initials: J
authors.lastname: Okebe
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Augustine O
authors.initials: AO
authors.lastname: Ebonyi
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Madi
authors.initials: M
authors.lastname: Njie
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Simon
authors.initials: S
authors.lastname: Correa
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Shamanthi
authors.initials: S
authors.lastname: Jayasooriya
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford, United Kingdom.
authors.forename: Climent
authors.initials: C
authors.lastname: Casals-Pascual
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton Cambridge, United Kingdom.
authors.forename: Oliver
authors.initials: O
authors.lastname: Billker
authors.affiliation: MRC Unit, Fajara, The Gambia; London School of Hygiene and Tropical Medicine, Bloomsbury, London, United Kingdom.
authors.forename: David J
authors.initials: DJ
authors.lastname: Conway
authors.affiliation: MRC Unit, Fajara, The Gambia.
authors.forename: Michael
authors.initials: M
authors.lastname: Walther
authors.affiliation: Laboratory of Malaria and Vector Research, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America.
authors.forename: Hans
authors.initials: H
authors.lastname: Ackerman
mesh_terms: D000581:Amidohydrolases / Q000097:blood*; D000818:Animals; D001120:Arginine / Q000097:blood*; D016022:Case-Control Studies; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism; D005714:Gambia; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008288:Malaria / Q000378:metabolism*; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*
chemical_list: D009569:Nitric Oxide; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase