title: N-Acetylcysteine prevents congenital heart defects induced by pregestational diabetes.
abstract: BACKGROUND
  Pregestational 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.
  
  
  METHODS
  Female 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.
  
  
  RESULTS
  Our 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.
  
  
  CONCLUSIONS
  Treatment 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.
authors.forename: Hoda
authors.initials: H
authors.lastname: Moazzen
authors.forename: Xiangru
authors.initials: X
authors.lastname: Lu
authors.forename: Noelle L
authors.initials: NL
authors.lastname: Ma
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Velenosi
authors.forename: Brad L
authors.initials: BL
authors.lastname: Urquhart
authors.forename: Lambertus J
authors.initials: LJ
authors.lastname: Wisse
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Gittenberger-de Groot
authors.affiliation: Department of Physiology and Pharmacology, University of Western Ontario, London, Ontario N6A 5C1, Canada. qfeng@uwo.ca.
authors.forename: Qingping
authors.initials: Q
authors.lastname: Feng
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage*; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000008:administration & dosage*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006330:Heart Defects, Congenital / Q000097:blood / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011247:Pregnancy; D011254:Pregnancy in Diabetics / Q000097:blood / Q000188:drug therapy / Q000473:pathology
chemical_list: D001786:Blood Glucose; D002316:Cardiotonic Agents; D000111:Acetylcysteine