Dimethylarginines: Endogenous Inhibitors of Nitric Oxide Synthesis in Children With Falciparum Malaria
| Autor: | Jackson Mukemba, Hao Wang, Donald L. Granger, Alicia D. Volkheimer, Tsin W. Yeo, Esther D. Mwaikambo, Matthew P. Rubach, Youwei Chen, Salvatore M. Florence, Nicholas M. Anstey, J B Weinberg |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Male
Arginine Biology Pharmacology Nitric Oxide Endothelial activation Hemoglobins Major Articles and Brief Reports chemistry.chemical_compound parasitic diseases medicine Humans Immunology and Allergy Malaria Falciparum Endothelial dysfunction Child Arginine transport Arginase medicine.disease Hypoargininemia Infectious Diseases chemistry Case-Control Studies Child Preschool Acute Disease Immunology Female Asymmetric dimethylarginine Malaria |
| Zdroj: | The Journal of Infectious Diseases. 210:913-922 |
| ISSN: | 1537-6613 0022-1899 |
| Popis: | Falciparum malaria remains a significant problem worldwide causing over 0.6 million deaths yearly, mostly in children [1, 2]. New insights into malaria pathophysiology and new treatments are needed. Nitric oxide (NO) is important in resistance to severe falciparum malaria, and there is markedly diminished NO bioavailability in falciparum malaria both adults and children [3, 4]. We have identified several processes contributing to the NO insufficiency ([5] for review). Recently, we found Indonesian adults with severe falciparum malaria had elevated plasma levels of endogenous methylated arginines [asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA)] and that ADMA levels correlated with decreased NO production, endothelial dysfunction, disease severity, and mortality [6]. Dimethylarginines are formed primarily as a result of protein breakdown (eg, in muscle or erythrocytes) and release of methylated arginine residues [7, 8]. High levels of ADMA and SDMA are predictive of poor outcomes in a variety of diseases including coronary artery disease, peripheral vascular disease, renal failure, sepsis, and malaria in Asian adults [7, 9, 10]. ADMA is a competitive inhibitor of NO synthases (NOS), and the ratio of plasma arginine to ADMA is a measure of arginine bioavailability to NOS. SDMA is not active as an inhibitor of NOS, but at supraphysiological concentrations it reduces arginine transport into cells by competitive inhibition of the cationic transporter (CAT2) [11] and enhances oxidative stress and inflammatory mediator release by macrophage-like cells [7, 12]. A recent study evaluating whole genome sequences of African children with falciparum malaria found polymorphisms of the enzyme dimethylarginine-dimethylaminohydrolase-1 (DDAH), which metabolizes ADMA to be associated with an increased risk of severe disease. However, no studies to our knowledge have measured concentrations of dimethylarginines in children with malaria to date, and the relationship with disease severity is not known. The purpose of the current study was to determine whether, as in Asian adults, plasma dimethylarginines are also increased in African children with falciparum malaria in proportion to disease severity and whether impaired L-arginine bioavailability (reflected by the arginine:ADMA ratio) would be associated with markers of impaired perfusion and endothelial activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|