Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis
| Autor: | Climent Casals-Pascual, Allison K. Ikeda, Simon Correa, Glenn Nardone, Hans Ackerman, Shamanthi Jayasooriya, David J. Conway, Aubrey J. Cunnington, Oliver Billker, Matthew S. Alkaitis, Madi Njie, Augustine O. Ebonyi, Jessica H. Chertow, Joseph Okebe, Michael Walther |
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| Přispěvatelé: | Universitat de Barcelona |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Arginine
Cell- och molekylärbiologi Homeòstasi 030204 cardiovascular system & hematology Blood plasma Pathogenesis Mice chemistry.chemical_compound 0302 clinical medicine Homeostasis Biology (General) 0303 health sciences 3. Good health Nitric oxide synthase medicine.anatomical_structure Liver Gambia Arginine homeostasis Research Article medicine.medical_specialty Endothelium QH301-705.5 Immunology Malària Biology Nitric Oxide Microbiology Amidohydrolases Nitric oxide 03 medical and health sciences Virology Internal medicine parasitic diseases Genetics medicine Animals Humans Plasmodium berghei Molecular Biology 030304 developmental biology Plasma sanguini RC581-607 biology.organism_classification Malaria Disease Models Animal Endocrinology chemistry Case-Control Studies biology.protein Parasitology Endothelium Vascular Immunologic diseases. Allergy Asymmetric dimethylarginine Cell and Molecular Biology |
| Zdroj: | PLoS Pathogens, Vol 11, Iss 9, p e1005119 (2015) Dipòsit Digital de la UB Universidad de Barcelona Recercat. Dipósit de la Recerca de Catalunya instname PLoS Pathogens |
| ISSN: | 1553-7374 1553-7366 |
| Popis: | 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 Author Summary During a malaria infection, the vascular endothelium becomes more adhesive, permeable, and prone to trigger blood clotting. These changes help the parasite adhere to blood vessels, but endanger the host by obstructing blood flow through small vessels. Endothelial nitric oxide (NO) would normally counteract these pathological changes, but NO signalling is diminished malaria. NO synthesis is inhibited by asymmetric dimethylarginine (ADMA), a methylated derivative of arginine that is released during normal protein turnover. We found the ratio of ADMA to arginine to be elevated in Gambian children with severe malaria, a metabolic disturbance known to inhibit NO synthesis. ADMA was associated with markers of endothelial activation and impaired tissue perfusion. In parallel experiments using mice, the enzyme responsible for metabolizing ADMA, dimethylarginine dimethylaminohydrolase (DDAH), was inactivated after infection with a rodent malaria. Based on these studies, we propose that decreased metabolism of ADMA by DDAH might contribute to the elevated ADMA/arginine ratio observed during an acute episode of malaria. Strategies to preserve or increase DDAH activity might improve NO synthesis and help to prevent the vascular manifestations of severe malaria. |
| Databáze: | OpenAIRE |
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