Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

Basu, Madhumita; Zhu, Jun-yi; LaHaye, Stephanie; Majumdar, Uddalak; Jiao, Kai; Han, Zhe; Garg, Vidu

doi:10.1172/jci.insight.95085

Cited by 71 publications

(94 citation statements)

References 83 publications

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“…However, whether maternal exercise may lead to up‐regulation of endogenous antioxidants and/or, reduced ROS production due to improved mitochondrial efficiency in our model remains to be studied. Notably, eNOS‐derived NO promotes Notch signalling, cell proliferation, EMT and differentiation during heart development, and has been implicated to play a role in ROS handling . In the present study, although there was no difference in the total eNOS protein levels between all four groups, levels of phosphorylated eNOS varied, being the lowest in OMD and highest in the two groups with maternal exercise.…”

Section: Discussioncontrasting

confidence: 60%

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Saiyin

Greco

Kim

et al. 2019

J Cellular Molecular Medi

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Women with pre‐gestational diabetes have a higher risk of producing children with congenital heart defects (CHDs), caused predominantly by hyperglycemia‐induced oxidative stress. In this study, we evaluated if exercise during pregnancy could mitigate oxidative stress and reduce the incidence of CHDs in the offspring of diabetic mice. Female mice were treated with streptozotocin to induce pre‐gestational diabetes, then mated with healthy males to produce offspring. They were also given access to running wheels 1 week before mating and allowed to exercise voluntarily until E18.5. Heart morphology, gene expression, and oxidative stress were assessed in foetal hearts. Maternal voluntary exercise results in a significantly lower incidence of CHDs from 59.5% to 25%. Additionally, diabetes‐induced defects in coronary artery and capillary morphogenesis were also lower with exercise. Myocardial cell proliferation and epithelial‐mesenchymal transition at E12.5 was significantly lower with pre‐gestational diabetes which was mitigated with maternal exercise. Cardiac gene expression of Notch1 , Snail1 , Gata4 and Cyclin D1 was significantly higher in the embryos of diabetic mice that exercised compared to the non‐exercised group. Furthermore, maternal exercise produced lower reactive oxygen species (ROS) and oxidative stress in the foetal heart. In conclusion, maternal exercise mitigates ROS and oxidative damage in the foetal heart, and results in a lower incidence of CHDs in the offspring of pre‐gestational diabetes. Exercise may be an effective intervention to compliment clinical management and further minimize CHD risk in mothers with diabetes.

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Section: Discussioncontrasting

confidence: 60%

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Saiyin

Greco

Kim

et al. 2019

J Cellular Molecular Medi

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“…In contrast, we and others have postulated parallel mechanisms for eNOS downregulation in response to hyperglycemia. Specifically, we demonstrated relative chromatin inaccessibility at eNOS loci by ATAC-sequencing and others have shown decreased phosphorylation at Ser1177 to reduce NO bioavailability under hyperglycemic stress (Chen et al, 2007; Basu et al, 2017). Supplementation with exogenous NO donor rather than antioxidants (such as NAC) was able to restore Jarid2 mediated Notch1 suppression in murine embryonic AV cushion mesenchymal (AVM) cell line and rescued hyperglycemia-mediated senescence, impaired migration and tube formation of late endothelial progenitor cells, suggesting an oxidative stress independent teratogenicity of hyperglycemia (Chen et al, 2007; Basu et al, 2017).…”

Section: Molecular Pathways Dysregulated In the Heart With Exposure Tmentioning

confidence: 60%

“…Specifically, we demonstrated relative chromatin inaccessibility at eNOS loci by ATAC-sequencing and others have shown decreased phosphorylation at Ser1177 to reduce NO bioavailability under hyperglycemic stress (Chen et al, 2007; Basu et al, 2017). Supplementation with exogenous NO donor rather than antioxidants (such as NAC) was able to restore Jarid2 mediated Notch1 suppression in murine embryonic AV cushion mesenchymal (AVM) cell line and rescued hyperglycemia-mediated senescence, impaired migration and tube formation of late endothelial progenitor cells, suggesting an oxidative stress independent teratogenicity of hyperglycemia (Chen et al, 2007; Basu et al, 2017). Previous studies have shown that global deletion of eNOS in mice results in CHD and eNOS −/− ; Notch1 +/− compound mutant mice exhibit a range of conotruncal and semilunar valve malformations, demonstrating the requirement of endothelial NO for proper heart development (Lee et al, 2000; Feng et al, 2002; Bosse et al, 2013).…”

Section: Molecular Pathways Dysregulated In the Heart With Exposure Tmentioning

confidence: 60%

“…CHD associated with matDM was shown to be completely rescued by reducing glutathione (GSH) and ROS levels by N-acetyl cysteine (NAC) treatment, and consistent with this, there was restoration of Gata4, Gata5 and Vegfa expression in the fetal heart of matDM offspring (Moazzen et al, 2014). However, conflicting results exist that show only a partial rescue with NAC treatment and that NAC can increase apoptosis and induce ~10% septal defects in control embryos suggesting that alternative mechanisms disrupting cardiac developmental pathways may also be present (Moazzen et al, 2014; Basu et al, 2017). Increased production of mitochondrial ROS has also been shown to disrupt endogenous antioxidant activities, trigger caspase3/8-dependent apoptosis and reduce cell proliferation in embryonic hearts exposed to matDM (Sivan et al, 1997; Morgan et al, 2008; Wentzel et al, 2008; Li et al, 2011; Wang et al, 2015).…”

Section: Molecular Pathways Dysregulated In the Heart With Exposure Tmentioning

confidence: 99%

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Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

Basu

Garg

2018

Birth Defects Research

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120

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Congenital heart disease (CHD) is the most common type of birth defect and is both a significant pediatric and adult health problem, in light of a growing population of survivors. The etiology of CHD has been considered to be multifactorial with genetic and environmental factors playing important roles. The combination of advances in cardiac developmental biology, which have resulted in the elucidation of molecular pathways regulating normal cardiac morphogenesis, and genome sequencing technology have allowed the discovery of numerous genetic contributors of CHD ranging from chromosomal abnormalities to single gene variants. On the other hand, mechanistic details of the contribution of environmental factors to CHD remain unknown. Maternal diabetes mellitus (matDM) is a well-established and increasingly prevalent environmental risk factor for CHD, but the underlying etiologic mechanisms by which pre-gestational matDM increases the vulnerability of embryos to cardiac malformations remains largely elusive. Here, we will briefly discuss the multifactorial etiology of CHD with a focus on the epidemiologic link between matDM and CHD. We will describe the animal models used to study the underlying mechanisms between matDM and CHD and review the numerous cellular and molecular pathways affected by maternal hyperglycemia in the developing heart. Lastly, we discuss how this increased understanding may open the door for the development of novel prevention strategies to reduce the incidence of CHD in this high-risk population.

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“…One potential mechanism behind an increasing risk of cardiac defects with higher glycated haemoglobin levels is that hyperglycaemia induces the expression of genes the products of which may influence the development of the heart in the fetus 30 ; hyperglycaemia may also work through oxidative stress leading to mitochondrial dysfunction and apoptosis, thereby leading to cardiac defects. 31 …”

Section: Discussionmentioning

confidence: 99%

Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden

Ludvigsson

Neovius

Söderling

et al. 2018

BMJ

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ObjectiveTo examine the association between maternal type 1 diabetes and the risk of major birth defects according to levels of glycated haemoglobin (HbA1C) within three months before or after estimated conception.DesignPopulation based historical cohort study using nationwide health registers.SettingSweden, 2003-15.Participants2458 singleton liveborn infants of mothers with type 1 diabetes and a glycated haemoglobin measurement within three months before or after estimated conception and 1 159 865 infants of mothers without diabetes.Main outcome measuresMajor cardiac and non-cardiac birth defects according to glycated haemoglobin levels.Results122 cases of major cardiac defects were observed among 2458 infants of mothers with type 1 diabetes. Compared with 15 cases of major cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 33 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 2.17, 95% confidence interval 1.37 to 3.42), 49 per 1000 for 6.5% to <7.8% (3.17, 2.45 to 4.11), 44 per 1000 for 7.8% to <9.1% (2.79, 1.90 to 4.12), and 101 per 1000 for ≥9.1% (6.23, 4.32 to 9.00). The corresponding adjusted risk differences were 17 (5 to 36), 32 (21 to 46), 26 (13 to 46), and 77 (49 to 118) cases of major cardiac defects per 1000 infants, respectively. 50 cases of major non-cardiac defects were observed among infants of mothers with type 1 diabetes. Compared with 18 cases of major non-cardiac defects per 1000 infants of mothers without diabetes, the rates among infants of mothers with type 1 diabetes were 22 per 1000 for a glycated haemoglobin level of <6.5% (adjusted risk ratio 1.18, 0.68 to 2.07), 19 per 1000 for 6.5% to <7.8% (1.01, 0.66 to 1.54), 17 per 1000 for 7.8% to <9.1% (0.89, 0.46 to 1.69), and 32 per 1000 for ≥9.1% (1.68, 0.85 to 3.33).ConclusionAmong liveborn infants of mothers with type 1 diabetes, increasingly worse glycaemic control in the three months before or after estimated conception was associated with a progressively increased risk of major cardiac defects. Even with glycated haemoglobin within target levels recommended by guidelines (<6.5%), the risk of major cardiac defects was increased more than twofold. The risk of major non-cardiac defects was not statistically significantly increased at any of the four glycated haemoglobin levels examined; the study had limited statistical power for this outcome and was based on live births only.

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Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease

Cited by 71 publications

References 83 publications

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Maternal voluntary exercise mitigates oxidative stress and incidence of congenital heart defects in pre‐gestational diabetes

Maternal hyperglycemia and fetal cardiac development: Clinical impact and underlying mechanisms

Periconception glycaemic control in women with type 1 diabetes and risk of major birth defects: population based cohort study in Sweden

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