Pregestational diabetes induces fetal coronary artery malformation via reactive oxygen species signaling

Diabetes. 2015 Apr;64(4):1431-43. doi: 10.2337/db14-0190. Epub 2014 Nov 24.


Hypoplastic coronary artery disease is a congenital coronary artery malformation associated with a high risk of sudden cardiac death. However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Pregestational diabetes increases reactive oxygen species (ROS) levels and the risk of congenital heart defects. We show that pregestational diabetes in mice induced by streptozotocin significantly increased 4-hydroxynonenal production and decreased coronary artery volume in fetal hearts. Pregestational diabetes also impaired epicardial epithelial-to-mesenchymal transition (EMT) as shown by analyses of the epicardium, epicardial-derived cells, and fate mapping. Additionally, the expression of hypoxia-inducible factor 1α (Hif-1α), Snail1, Slug, basic fibroblast growth factor (bFgf), and retinaldehyde dehydrogenase (Aldh1a2) was decreased and E-cadherin expression was increased in the hearts of fetuses of diabetic mothers. Of note, these abnormalities were all rescued by treatment with N-acetylcysteine (NAC) in diabetic females during gestation. Ex vivo analysis showed that high glucose levels inhibited epicardial EMT, which was reversed by NAC treatment. We conclude that pregestational diabetes in mice can cause coronary artery malformation through ROS signaling. This study may provide a rationale for further clinical studies to investigate whether pregestational diabetes could cause hypoplastic coronary artery disease in humans.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase 1 Family
  • Aldehydes / metabolism
  • Animals
  • Blood Glucose
  • Cadherins / metabolism
  • Coronary Vessel Anomalies / etiology*
  • Coronary Vessel Anomalies / metabolism
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / metabolism
  • Epithelial-Mesenchymal Transition
  • Female
  • Fibroblast Growth Factor 2 / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Isoenzymes / metabolism
  • Mice
  • Myocardium / metabolism
  • Pregnancy
  • Prenatal Exposure Delayed Effects / metabolism*
  • Reactive Oxygen Species / metabolism*
  • Retinal Dehydrogenase / metabolism
  • Signal Transduction / physiology


  • Aldehydes
  • Blood Glucose
  • Cadherins
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Isoenzymes
  • Reactive Oxygen Species
  • Fibroblast Growth Factor 2
  • Aldehyde Dehydrogenase 1 Family
  • ALDH1A1 protein, human
  • ALDH1A1 protein, mouse
  • Retinal Dehydrogenase
  • 4-hydroxy-2-nonenal