Decreased NO Bioavailability Leading to Endothelial Dysfunction in Children with ALL Results From Increased eNOS Inhibiting by Asymmetrical Dimethylarginine and May Be Associated with Increased Mortality

Endothelial dysfunction worsens the prognosis in numerous severe diseases. Impaired vascular reactivity, increased procoagulative and proinflammatory action are commonly observed when the nitric oxide bioavailability is limited. Asymmetrical dimethylarginine (ADMA) is a competive inhibitor of the endothelial nitric oxide synthase (eNOS). ADMA is produced during proteolysis of methylated proteins, especially histones. The aim this study was to determine if ADMA may play important role in pathogenesis of endothelial dysfunction in children with ALL.

N=14 children at age of 4–18 years with ALL treated with the ALLIC protocol were investigated. Plasma levels of the NO pathway metabolites (L-Arginine, ADMA) were analyzed at baseline, then during the 33^rd and 78^th day of protocol. The control group constituted of N=14, age-matched healthy children.

Plasma ADMA levels were significantly higher in children with ALL at baseline as compared to the control group (1.92±0.42 vs. 0.56±0.1 ng/ml, p<0.05), and were significantly decreasing to 0.63±0.15ng/ml, p<0.05 following the steroid therapy. During the 78^th day the ADMA levels were maintained at similar levels as compared to the 33^rd day. Opposite trends were observed with the L-Arginine levels and the L-Arg/ADMA ratio reflecting the NO synthesis. L-Arg and L-Arg/ADMA ratio were significantly lower in children with ALL at baseline vs. control group (41.65±4.12vs.52.4±2.31pg/ml and 28.7±6.61vs.83.41±14.13, respectively, p<0.05). Moreover, the L-Arg/ADMA ratio at the 78^th day was significantly higer in cases treated unsuccesfully in comparison with those who survived (88.1±21.3vs.43.0±10.2, p<0.05).

Decreased NO bioavailability in children with ALL at baseline results from the eNOS inhibiting by ADMA and may be associated with increased mortality.

No relevant conflicts of interest to declare.