{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Choudhury TZ"],"funding":["NHLBI NIH HHS","National Institutes of Health","National Institutes of Health/  National Heart, Lung, and Blood Institute"],"pagination":["e183516"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11623948"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["9(23)"],"pubmed_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."],"journal":["JCI insight"],"pubmed_title":["Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease."],"pmcid":["PMC11623948"],"funding_grant_id":["R01 HL155282","T32 HL166149","R01 HL144009","R01HL144009"],"pubmed_authors":["Girard HB","Choudhury TZ","Garg V","Budhathoki Y","Rao AS","Li D","Zhao MT","Greskovich SC","Cameron EM","Conroy S"],"additional_accession":[]},"is_claimable":false,"name":"Impact of genetic factors on antioxidant rescue of maternal diabetes-associated congenital heart disease.","description":"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.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Dec","modification":"2026-06-03T00:54:02.047Z","creation":"2025-04-06T15:07:28.133Z"},"accession":"S-EPMC11623948","cross_references":{"pubmed":["39437002"],"doi":["10.1172/jci.insight.183516"]}}