{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T20:08:45Z","timestamp":1778098125242,"version":"3.51.4"},"reference-count":207,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000024","name":"Canadian Institutes of Health Research","doi-asserted-by":"publisher","award":["MOP-142383"],"award-info":[{"award-number":["MOP-142383"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["06581"],"award-info":[{"award-number":["06581"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. In experimental animal models of pregestational diabetes induced-CHDs, upwards of 50% of offspring display congenital malformations of the heart, including septal, valvular, and outflow tract defects. Specifically, the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) signaling is a major driver of the development of CHDs in offspring of mice with pregestational diabetes. NO from endothelial nitric oxide synthase (eNOS) is crucial to cardiogenesis, regulating various cellular and molecular processes. In fact, deficiency in eNOS results in CHDs and coronary artery malformation. Embryonic hearts from diabetic dams exhibit eNOS uncoupling and oxidative stress. Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes.<\/jats:p>","DOI":"10.3390\/antiox8100436","type":"journal-article","created":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T11:11:16Z","timestamp":1569928276000},"page":"436","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":42,"title":["Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes"],"prefix":"10.3390","volume":"8","author":[{"given":"Anish","family":"Engineer","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4215-6017","authenticated-orcid":false,"given":"Tana","family":"Saiyin","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elizabeth R.","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9739-2765","authenticated-orcid":false,"given":"Qingping","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, Western University, London, Ontario, ON N6A 5C1, Canada"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,10,1]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3015","DOI":"10.1161\/CIRCULATIONAHA.106.183056","article-title":"Genetic basis for congenital heart defects: Current knowledge: A scientific statement from the American Heart Association Congenital Cardiac Defects Committee, Council on Cardiovascular Disease in the Young: Endorsed by the American Academy of Pediatrics","volume":"115","author":"Pierpont","year":"2007","journal-title":"Circulation"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1161\/CIRCULATIONAHA.115.019307","article-title":"Congenital heart defects in the United States: Estimating the magnitude of the affected population in 2010","volume":"134","author":"Gilboa","year":"2016","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e67","DOI":"10.1161\/CIR.0000000000000558","article-title":"Heart disease and stroke statistics-2018 update: A report from the American Heart Association","volume":"137","author":"Benjamin","year":"2018","journal-title":"Circulation"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1002\/bdra.10119","article-title":"First-year survival of infants born with congenital heart defects in Arkansas (1993\u20131998): A survival analysis using registry data","volume":"67","author":"Cleves","year":"2003","journal-title":"Birth Defects Res. 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