The developing embryonic cardiac outflow tract is highly sensitive to oxidant stress

Abstract

This study tested the hypothesis that the remodeling of the cardiac outflow tract (OFT) may represent a developmental window of vulnerability to reactive oxygen species (ROS). Chick embryos were exposed in ovo or ex ovo to increasing concentrations of the stable oxidant hydrogen peroxide (H2O2). As assessed by trypan blue staining, H2O2 induced cell injury in the stage 25-30 OFT at concentrations as low as 1 nM. Higher concentrations were required to induce cell injury in the ventricular and atrial myocardium. Using DCFDA as an indicator of oxidant stress, H2O2 also induced a greater fluorescent signal in the OFT myocardium. H2O2 at these low concentrations also induced Caspase activity, indicative of activation of the pathway of PCD. Interestingly, the induction of Caspase-3 activity was predominately in the OFT cushion mesenchymal cells. Thus, the developing OFT is particularly sensitive to ROS-mediated injury, suggesting that ROS could play a role in the development of congenital defects of the cardiac OFT. Developmental Dynamics 236:3496 -3502, 2007.

Male gender significantly increases risk of oxidative stress related congenital anomalies in the non-diabetic population

“…The developing cardiac outflow tract was shown to be particularly sensitive to ROS-mediated injury implicating ROS in heart defects involving the outflow tracts in developing chicks [23]. One of the most important mechanisms by which diabetes is thought to induce anomalies is through the generation of OS [4,5].…”

Epithelial-to-Mesenchymal and Endothelial-to-Mesenchymal Transition

“…93 In addition, cushion mesenchymal cells are especially sensitive to reactive oxygen species-mediated injury, suggesting that oxidative stress may contribute to the formation of congenital cardiac defects. 94 …”

Differential contribution of mitochondria, NADPH oxidases, and glycolysis to region-specific oxidant stress in the anoxic-reoxygenated embryonic heart

“…The time course of ROS production was comparable in the atria and ventricle but notably differed from that in the outflow tract (conotruncus). At the stage investigated, the outflow tract is subjected to extensive and physiological programmed cell death (89), is a hypoxic zone (75,96), is highly sensitive to oxidant stress induced by H 2 O 2 (28), and contains ϳ2.5-fold less glycogen than the ventricle and atria (58). It is conceivable that the capacity of ROS detoxification in the intensively remodeling outflow tract is lower than in the atria and ventricle, with the antioxidant systems being rapidly overwhelmed upon reoxygenation when acceleration of ROS production is maximal (Fig.…”

“…Indeed, throughout cardiogenesis, the atria differentiate into pacemaker tissue, the ventricle differentiates into the working myocardium, and the outflow tract (conotruncus) undergoes critical remodeling, preparing the aorticopulmonary septation. The outflow tract is especially vulnerable to stresses such as hypoxia (acute or chronic) or oxidative stress (28,75), and morphogenetic disturbances in this region account for one-third of all congenital heart defects. However, to what extent the atria, ventricle, and outflow tract share similar pro-and antioxidant properties and show distinct profiles of ROS production during anoxia-reoxygenation remain unexplored.…”