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

Abstract

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 epithelialto-mesenchymal transition (EMT) as shown by analyses of the epicardium, epicardial-derived cells, and fate mapping. Additionally, the expression of hypoxia-inducible factor 1a (Hif-1a), 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.Pregestational diabetes is a risk factor for congenital heart defects in infants (1,2). Clinical studies have shown that pregestational diabetes increases the risk of congenital heart defects in the offspring by three-to fivefold compared with nondiabetic pregnancies (1-3). To date, analysis of congenital heart malformation in the newborn is mainly restricted to major cardiac structures, which include the aorta, pulmonary artery, atrioventricular septum, cardiac valves, and myocardium, but coronary arteries are not routinely examined (4). Congenital malformation can occur in the coronary arteries, leading to null coronary artery or hypoplastic coronary artery disease (5). Although null coronary artery is embryonically lethal, hypoplastic coronary artery disease is a rare congenital coronary abnormality defined by malformation of one or more major branches of the coronary arteries with a marked decrease in luminal diameter and length. Hypoplastic coronary artery disease can be asymptomatic but often is associated with myocardial infarction and sudden cardiac death during intense physical activity (6). However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Furthermore, it is not known whether pregestational diabetes results in coronary artery malformation in offspring. Isolated cases of congenital coronary artery abnormalities have been identified in infants by autopsy. However, whether the mothers of these infants had pregestational diabetes was not disclosed in these reports (7,8). A large multicenter case-control study sho...

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