{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T23:48:14Z","timestamp":1792280894726,"version":"4.4.0"},"reference-count":125,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"9","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2025,5,6]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">Congenital heart disease is a leading cause of death in newborns, yet many of its molecular mechanisms remain unknown. Both maternal obesity and diabetes increase the risk of congenital heart disease in offspring, with recent studies suggesting these conditions may have distinct teratogenic mechanisms. The global prevalence of obesity is rising, and while maternal obesity is a known risk factor for fetal congenital heart disease, the specific mechanisms are largely unexplored.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods and Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">We used a murine model of diet\u2010induced maternal obesity, without diabetes, to produce dams that were overweight but had normal blood glucose levels. Embryos were generated and their developing hearts analyzed. Transcriptome analysis was performed using single\u2010nucleus and bulk RNA sequencing. Global and phospho\u2010enriched proteome analysis was performed using tandem mass tag\u2013mass spectroscopy. Immunobloting and histologic evaluation were also performed.<\/jats:p>\n                    <jats:p xml:lang=\"en\">\n                      Analysis revealed disrupted oxidative phosphorylation and reactive oxygen species formation, with reduced antioxidant capacity, evidenced by downregulation of genes\n                      <jats:italic toggle=\"no\">Sod1<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"no\">Gp4x<\/jats:italic>\n                      , and disrupted\n                      <jats:italic toggle=\"no\">Hif1a<\/jats:italic>\n                      signaling. Evidence of oxidative stress, cell death signaling, and alteration in Rho GTPase and actin cytoskeleton signaling was also observed. Genes involved in cardiac morphogenesis, including\n                      <jats:italic toggle=\"no\">Hand2<\/jats:italic>\n                      , were downregulated, and fewer mature cardiomyocytes were present. Histologic analysis confirmed increased cardiac defects in embryos exposed to maternal obesity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">These findings demonstrate that maternal obesity alone can result in cardiac defects through mechanisms similar to those associated with maternal hyperglycemia. This study provides valuable insight into the role of maternal obesity, a growing and modifiable risk factor, in the development of the most common birth defect, congenital heart disease.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.124.039684","type":"journal-article","created":{"date-parts":[[2025,5,2]],"date-time":"2025-05-02T07:59:59Z","timestamp":1746172799000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":18,"title":["Role of Maternal Obesity in Offspring Cardiovascular Development and Congenital Heart Defects"],"prefix":"10.1161","volume":"14","author":[{"given":"Ashleigh","family":"McMullan","sequence":"first","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7027-0916","authenticated-orcid":false,"given":"James B.","family":"Zwierzynski","sequence":"additional","affiliation":[{"name":"Stanford University","place":["Stanford, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5347-8539","authenticated-orcid":false,"given":"Nina","family":"Jain","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura S.","family":"Haneline","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5538-9605","authenticated-orcid":false,"given":"Weinian","family":"Shou","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6351-4506","authenticated-orcid":false,"given":"Kok Lim","family":"Kua","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]},{"name":"Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3105-9729","authenticated-orcid":false,"given":"Swetansu K.","family":"Hota","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1686-903X","authenticated-orcid":false,"given":"Matthew D.","family":"Durbin","sequence":"additional","affiliation":[{"name":"Herman B Wells Center for Pediatric Research, Indiana University School of Medicine","place":["Indianapolis, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.103.19.2376"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.5935\/abc.20180175"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpeds.2008.05.059"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2012-3435"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.08.025"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.112.300853"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006906"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1101\/cshperspect.a037234"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13052-014-0085-3"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/chd.12567"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.3945\/ajcn.2009.28865"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/1315796"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.j2563"},{"key":"e_1_3_2_15_2","doi-asserted-by":"crossref","unstructured":"Rosenbluh O Walfisch A. 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