TY - JOUR
T1 - Dimethylarginines: Endogenous inhibitors of nitric oxide synthesis in children with falciparum malaria
AU - Weinberg, Joe
AU - Yeo, Tsin
AU - Mukemba, Jackson
AU - Florence, Salvatore
AU - Volkheimer, Alicia
AU - Wang, Hao
AU - Chen, Youwei
AU - Rubach, Matthew
AU - Granger, Donald
AU - Mwaikambo, Esther
AU - Anstey, Nicholas
PY - 2014/9/15
Y1 - 2014/9/15
N2 - Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown. Methods. We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cellfree hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured. Results. ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine: ADMA ratio normalized, but SDMA did not. Arginine: ADMA ratios, but not arginine, were significantly and independently inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria. Conclusions. In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.
AB - Nitric oxide (NO) bioavailability is impaired in children and adults with severe falciparum malaria (SM). Asymmetric-dimethylarginine (ADMA) limits NO production by inhibiting NO synthase and is increased in adult SM. The role of ADMA in the pathogenesis of childhood SM is unknown. Methods. We studied Tanzanian children ages 4-8 years with malaria. Plasma levels of arginine, arginase, cellfree hemoglobin, ADMA, symmetric-dimethylarginine (SDMA), histidine-rich protein-2, and angiopoietin-2 were measured. Results. ADMA was low in children with SM relative to controls. Nevertheless, arginine and arginine:ADMA ratios were very low in SM. SDMA was high in children with SM. With treatment, arginine and the arginine: ADMA ratio normalized, but SDMA did not. Arginine: ADMA ratios, but not arginine, were significantly and independently inversely associated with lactate and angiopoietin-2. Plasma arginase was not elevated in those with malaria, and plasma free hemoglobin was elevated only in patients with cerebral malaria. Conclusions. In contrast to adults, plasma ADMA is reduced in SM in children, but hypoargininemia is more severe. Arginine bioavailability (reflected by low arginine:ADMA ratios) is therefore comparably low in SM in children as in adults. Therapies to increase NO bioavailability in malaria may be useful as adjunctive treatment of severe malaria in children.
KW - Angiopoeitin 2
KW - Arginase
KW - Arginine
KW - Asymmetric dimethylarginine
KW - Falciparum malaria
KW - Lactate
KW - Nitric oxide
KW - Symmetric dimethylarginine
UR - http://www.scopus.com/inward/record.url?scp=84906754006&partnerID=8YFLogxK
U2 - 10.1093/infdis/jiu156
DO - 10.1093/infdis/jiu156
M3 - Article
VL - 210
SP - 913
EP - 922
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
SN - 0022-1899
IS - 6
ER -