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Abstract
Congenital heart disease (CHD) affects approximately 1% of live births. Although genetic and environmental etiologic contributors have been identified, the majority of CHD lacks a definitive cause, suggesting the role of gene-environment interactions (GxEs) in disease pathogenesis. Maternal diabetes mellitus (matDM) is among the most prevalent environmental risk factors for CHD. However, there is a substantial knowledge gap in understanding how matDM acts upon susceptible genetic backgrounds to increase disease expressivity. Previously, we reported a GxE between Notch1 haploinsufficiency and matDM leading to increased CHD penetrance. Here, we demonstrate a cell lineage–specific effect of Notch1 haploinsufficiency in matDM-exposed embryos, implicating endothelial/endocardial tissues in the developing heart. We report impaired atrioventricular cushion morphogenesis in matDM-exposed Notch1+/– animals and show a synergistic effect of NOTCH1 haploinsufficiency and oxidative stress in dysregulation of gene regulatory networks critical for endocardial cushion morphogenesis in vitro. Mitigation of matDM-associated oxidative stress via superoxide dismutase 1 overexpression did not rescue CHD in Notch1-haploinsufficient mice compared to wild-type littermates. Our results show the combinatorial interaction of matDM-associated oxidative stress and a genetic predisposition, Notch1 haploinsufficiency, on cardiac development, supporting a GxE model for CHD etiology and suggesting that antioxidant strategies alone may be ineffective in genetically susceptible individuals.
Authors
Talita Z. Choudhury, Sarah C. Greskovich, Holly B. Girard, Anupama S. Rao, Yogesh Budhathoki, Emily M. Cameron, Sara Conroy, Deqiang Li, Ming-Tao Zhao, Vidu Garg
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