Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.
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...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2015-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1005119 |
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| author | Jessica H Chertow Matthew S Alkaitis Glenn Nardone Allison K Ikeda Aubrey J Cunnington Joseph Okebe Augustine O Ebonyi Madi Njie Simon Correa Shamanthi Jayasooriya Climent Casals-Pascual Oliver Billker David J Conway Michael Walther Hans Ackerman |
| author_facet | Jessica H Chertow Matthew S Alkaitis Glenn Nardone Allison K Ikeda Aubrey J Cunnington Joseph Okebe Augustine O Ebonyi Madi Njie Simon Correa Shamanthi Jayasooriya Climent Casals-Pascual Oliver Billker David J Conway Michael Walther Hans Ackerman |
| author_sort | Jessica H Chertow |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-6df109d8e2704dc1834e0a80da25a24b |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2015-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-6df109d8e2704dc1834e0a80da25a24b2025-08-20T03:46:12ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742015-09-01119e100511910.1371/journal.ppat.1005119Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis.Jessica H ChertowMatthew S AlkaitisGlenn NardoneAllison K IkedaAubrey J CunningtonJoseph OkebeAugustine O EbonyiMadi NjieSimon CorreaShamanthi JayasooriyaCliment Casals-PascualOliver BillkerDavid J ConwayMichael WaltherHans AckermanInhibition 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.https://doi.org/10.1371/journal.ppat.1005119 |
| spellingShingle | Jessica H Chertow Matthew S Alkaitis Glenn Nardone Allison K Ikeda Aubrey J Cunnington Joseph Okebe Augustine O Ebonyi Madi Njie Simon Correa Shamanthi Jayasooriya Climent Casals-Pascual Oliver Billker David J Conway Michael Walther Hans Ackerman Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. PLoS Pathogens |
| title | Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. |
| title_full | Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. |
| title_fullStr | Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. |
| title_full_unstemmed | Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. |
| title_short | Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis. |
| title_sort | plasmodium infection is associated with impaired hepatic dimethylarginine dimethylaminohydrolase activity and disruption of nitric oxide synthase inhibitor substrate homeostasis |
| url | https://doi.org/10.1371/journal.ppat.1005119 |
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