Plasmodium Infection Is Associated with Impaired Hepatic Dimethylarginine Dimethylaminohydrolase Activity and Disruption of Nitric Oxide Synthase Inhibitor/Substrate Homeostasis

• DOI: 10.1371/journal.ppat.1005119
• Publication Date: 2015-09-25T18:40:15Z
• Authors: Jessica H. Chertow; Matthew S. Alkaitis; Glenn Nardone; Allison K. Ikeda; Aubrey J. Cunnington; Joseph Okebe; Augustine O. Ebonyi; Madi Njie; Simon Correa; Shamanthi Jayasoo...; Climent Casals-Pa...; Oliver Billker; David J. Conway; Michael Walther; Hans Ackerman
• Keywords: Asymmetric dimethylarginine; Homeostasis; Pathogenesis

Inhibition of nitric oxide (NO) signaling may contribute to pathological activation the vascular endothelium during severe malaria infection. Dimethylarginine dimethylaminohydrolase (DDAH) regulates endothelial NO synthesis by maintaining homeostasis between asymmetric dimethylarginine (ADMA), an endogenous synthase (NOS) inhibitor, and arginine, NOS substrate. We carried out a community-based case-control study Gambian children determine whether ADMA arginine is disrupted or uncomplicated infections. Circulating plasma levels were determined at initial presentation 28 days later. Plasma ADMA/arginine ratios elevated in with acute compared 28-day follow-up values healthy (p<0.0001 for each comparison). To test hypothesis that DDAH1 inactivated Plasmodium infection, we examined mouse model malaria. berghei ANKA infection hepatic via post-transcriptional mechanism as evidenced stable mRNA transcript number, decreased protein concentration, enzyme activity, tissue ADMA, ratio plasma, whole blood nitrite concentration. Loss activity disruption pathogenesis inhibiting synthesis.