Elevated levels of macromolecular damage are correlated with increased nitric oxide synthase expression in erythrocytes isolated from twin neonates

Abstract

SummaryPregnancy is a state associated with an enhanced metabolism and demand for O 2 , which may lead to the overproduction of reactive oxygen species (ROS) and hence to oxidative stress. An elevated ROS level may result in delayed development and a low birth weight. The aim of this study was to reveal the consequences of multiple pregnancies on the redox status of neonatal human red blood cells (RBCs) and evaluate the role of endothelial nitric oxide synthase (NOS3) -expressing RBCs in the generation of oxidative stress. The study presents evidence of higher levels of production of hydrogen peroxide, peroxynitrite and nitrate content in the RBCs of twin neonates, clearly reflected by an elevated level of protein and lipid damages. This phenotype appears to be a consequence of multiple pregnancies, regardless of the level of maturity or the birth weight of the twins. Besides the higher level of ROS, there was a general decrease in the expression of genes coding for antioxidants. The first data are presented on NOS3-expressing neonatal human RBCs. The number of RBCs producing NOS3 was more than twice as high in twin neonates compared to singletons, with no correlation to maturity.

Mature Twin Neonates Exhibit Oxidative Stress via Nitric Oxide Synthase Dysfunctionality: A Prognostic Stress Marker in the Red Blood Cells and Umbilical Cord Vessels

“…Primarily, the NOS3 dimer formation and its phosphorylation at serine1177 residue are crucial criteria in the functional activation of NOS3 [ 17 ]. In accordance with our previous findings and recent publications, endogenous or the acquired exogenous antioxidant defense mechanisms are not fully functional, as the expression of genes coding for antioxidants are downregulated in the twin neonates with comparison to singletons [ 25 ]. On this background, the homeostatic balance between the prooxidant and antioxidant gets easily disrupted and the presence of excess ROS highly influence and regulate the NOS3 activation pathway by the induction of Arginase1 expression.…”

“…In that situation, NO plays an exceptionally crucial role in the process of vasorelaxation and sufficient blood supply to the fetus. In our previous study, we demonstrated an elevated NOS3 expressing population of RBCs in twin neonates compared to singletons [ 25 ]. Based on the data by Pernow et al [ 23 , 24 ], in the present study we looked for a cross-talk between circulating RBCs and vascular endothelium and focused on the detailed molecular mechanism of NO production not only limited to the RBC population, but also in the UC endothelium.…”

“…Previously, our working group demonstrated an increased ROS production and compromised antioxidant system with an increased level of NOS3, leading to elevated macromolecular damage in the fetal RBCs derived from twin neonates [ 25 ]. In continuation of this project and citing the intimate crosstalk in between the vascular endothelium and the circulating RBCs, we further elucidated the NOS3 regulation and activity in detail on the fetal RBCs from cord artery and endothelial cells of the umbilical cord derived from twin neonates and singletons.…”

Blunted Reducing Power Generation in Erythrocytes Contributes to Oxidative Stress in Prepubertal Obese Children with Insulin Resistance

“…Glutathione, for example, needs to be recycled (when oxidized) by glutathione reductase, an NADPH-dependent enzyme, and catalase is also NADPH-dependent to avoid inactivation [19]. Moreover, NADPH oxidase or inducible nitric oxide synthase (eNOS) activities are dependent on NADPH in the erythrocyte [20].…”

Nitric oxide synthase dysfunctionality in the umbilical cord vascular system during twin birth correlates with maturity and birth weight of the neonates

“…During long-term oxidative stress conditions like twin pregnancy, mapping the efficacy of the NOS pathway becomes pivotal in the regulation of bioavailable NO for vasorelaxation and free flow of blood supply within the cord vascular system. Previously, our working group pioneered in demonstrating an increased ROS production and compromised antioxidant system in parallel with the increased level of NOS3, leading to elevated macromolecular damage in the foetal RBCs of the twin neonates (Dugmonits et al, 2016). Therefore, now in a detailed comparative study, we attempted to elucidate the significance of intimate crosstalk in between the foetal RBCs and the cord vascular endothelium that involves the signalling pathway of NOS3 activation.…”