N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes

Abstract

BackgroundPregestational diabetes is a major risk factor of congenital heart defects (CHDs). Glutathione is depleted and reactive oxygen species (ROS) production is elevated in diabetes. In the present study, we aimed to examine whether treatment with N-acetylcysteine (NAC), which increases glutathione synthesis and inhibits ROS production, prevents CHDs induced by pregestational diabetes.MethodsFemale mice were treated with streptozotocin (STZ) to induce pregestational diabetes prior to breeding with normal males to produce offspring. Some diabetic mice were treated with N-acetylcysteine (NAC) in drinking water from E0.5 to the end of gestation or harvesting of the embryos. CHDs were identified by histology. ROS levels, cell proliferation and gene expression in the fetal heart were analyzed.ResultsOur data show that pregestational diabetes resulted in CHDs in 58% of the offspring, including ventricular septal defect (VSD), atrial septal defect (ASD), atrioventricular septal defects (AVSD), transposition of great arteries (TGA), double outlet right ventricle (DORV) and tetralogy of Fallot (TOF). Treatment with NAC in drinking water in pregestational diabetic mice completely eliminated the incidence of AVSD, TGA, TOF and significantly diminished the incidence of ASD and VSD. Furthermore, pregestational diabetes increased ROS, impaired cell proliferation, and altered Gata4, Gata5 and Vegf-a expression in the fetal heart of diabetic offspring, which were all prevented by NAC treatment.ConclusionsTreatment with NAC increases GSH levels, decreases ROS levels in the fetal heart and prevents the development of CHDs in the offspring of pregestational diabetes. Our study suggests that NAC may have therapeutic potential in the prevention of CHDs induced by pregestational diabetes.

Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

“…It has been shown that overexpression of the superoxide dismutase (SOD) gene rescues CHD phenotypes in the offspring of mice with matDM but this may overexpression system may have numerous effects apart from decreased ROS (68). Similarly, NAC treatment of severely diabetic mice (average blood glucose >450 mg/dl) has been shown to partially rescue the CHD phenotypes (69). This finding is not inconsistent with our data, as complete rescue was not achieved with NAC with moderate maternal HG (average blood glucose >200 mg/dl), and this is likely due to changes in chromatin accessibility at the Nos3 locus.…”

Pregestational Diabetes Induces Fetal Coronary Artery Malformation via Reactive Oxygen Species Signaling

“…Studies have shown that Wt1 directs epicardial progenitors to become smooth muscle cells and fibroblasts and forms coronary arteries (19). Pregestational diabetes increases reactive oxygen species (ROS) production (20,21) and downregulates HIF-1a expression in embryos (22). We have shown that treatment with N-acetylcysteine (NAC) increases reduced glutathione (GSH) levels and decreases ROS production in the hearts of fetuses of mice with pregestational diabetes (20).…”

Noninherited Risk Factors of Congenital Heart Defects in Offspring: A Revi

“…76 Experimental studies suggest that hyperglycemia during early embryogenesis may alter gene expression in key cellular components of the developing heart, in particular, the embryonic heart's outflow sections; however, the mechanism producing this altered gene expression is unclear. 16,17 Maternal infection during pregnancy and CHD Frequency of maternal urinary tract infections during pregnancy (5% to 9%, EST: +0.5% [+0.2%, +0.7%]/ year, P<0.001) is associated with CHD. 13 Prenatal maternal fever or influenza may be associated with right-sided obstructive lesions in all infants and with atrioventricular septal defects in infants with Down syndrome.…”