Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease

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

doi:10.1172/jci.insight.183516

Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease

Talita Z. Choudhury,¹ Sarah C. Greskovich,¹ Holly B. Girard,¹ Anupama S. Rao,¹ Yogesh Budhathoki,² Emily M. Cameron,³ Sara Conroy,⁴ Deqiang Li,¹ Ming-Tao Zhao,¹ and Vidu Garg¹

Published October 22, 2024 - More info

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Abstract

Congenital heart disease (CHD) affects ~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 (GxE) 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 derived 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 SOD1 overexpression did not rescue CHD in Notch1 haploinsufficient mice compared to wildtype 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 maybe ineffective in genetically-susceptible individuals.

Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease

Talita Z. Choudhury,¹ Sarah C. Greskovich,¹ Holly B. Girard,¹ Anupama S. Rao,¹ Yogesh Budhathoki,² Emily M. Cameron,³ Sara Conroy,⁴ Deqiang Li,¹ Ming-Tao Zhao,¹ and Vidu Garg¹

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Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease

Talita Z. Choudhury,1 Sarah C. Greskovich,1 Holly B. Girard,1 Anupama S. Rao,1 Yogesh Budhathoki,2 Emily M. Cameron,3 Sara Conroy,4 Deqiang Li,1 Ming-Tao Zhao,1 and Vidu Garg1

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Talita Z. Choudhury,¹ Sarah C. Greskovich,¹ Holly B. Girard,¹ Anupama S. Rao,¹ Yogesh Budhathoki,² Emily M. Cameron,³ Sara Conroy,⁴ Deqiang Li,¹ Ming-Tao Zhao,¹ and Vidu Garg¹