S -Nitrosylated fetal hemoglobin in neonatal human blood

Abstract

Background Nitric oxide (NO) and its derivatives play important roles in the cardiopulmonary transition upon birth and in other oxygen-sensitive developmental milestones. One mechanism for the coupling of oxygen sensing and signaling by NO species is via the formation of an S-nitrosothiol (SNO) moiety on hemoglobin (Hb, forming SNO-Hb) and its release from the red blood cell in hypoxia. Although SNO-Hb formed on adult-type Hb (HbA, forming SNO-HbA) has been documented in physiological and pathophysiological human states, the fetal variant, SNO-HbF, has thus far not been isolated or characterized in human blood. Methods and Results We developed a technique capable of separating Hbs A and F under conditions that preserve SNO. We then measured SNO-HbF in the blood of healthy and premature or otherwise ill neonates using the gold standard for SNO measurement, mercury-coupled photolysis-chemiluminescence. SNO-HbF levels were in the range of those previously reported for HbA in adults. We found that SNO-HbF was more abundant at earlier gestational age (<30 weeks), even when accounting for the absolute HbF level. Conclusions The ability to monitor SNO-HbF could provide new insights into fetal development and the perinatal transition, and has potential as a biomarker relevant to the management of neonatal diseases.

Modulation of the allosteric and vasoregulatory arms of erythrocytic oxygen transport

“…In particular, RBCs from a mouse model bearing human hemoglobin in which the β93 Cys residue was mutated to Ala (alanine) were reported to function normally. But this mouse was also engineered to express gamma hemoglobin [a component of fetal hemoglobin (HbF)], which we have shown is also reversibly S-nitrosylated ( Riccio et al, 2016 ); this rescue may account for the lack of phenotype in this mouse. By contrast, Zhang and coworkers demonstrated that even the persistence (or presence by knock-in) of SNO-susceptible fetal hemoglobin does not fully compensate for the mutation of the critical Cys normally present at residue 93 of the beta-globin subunit of hemoglobin ( Zhang et al, 2015 ).…”

S‐Nitroso‐l‐cysteine and ventilatory drive: A pediatric perspective

“…Second, l ‐CSNO and other S‐nitrosothiols appear to also play a role in the perinatal transition to air‐breathing 65 . Human HbF carries significant S‐nitrosothiol signaling potential, in addition to HbA, 66 , 67 and because the P 50 of HbF is lower (its oxygen affinity is higher), the oxygen tension at which NO is transferred to form S‐nitrosothiols is higher. Oxygen tensions are quite low before birth, shifting dramatically at birth.…”