Infants of mothers with diabetes have increased risk of congenital heart defects. Such developmental defects are likely caused by a combination of genetic and environmental factors. The molecular mechanisms by which maternal diabetes disrupts normal heart development in genetically susceptible individuals remain unclear.
The Cardiovascular Research describe a gene-environment interaction resulting in congenital heart defects in both mouse and fly model systems. Interaction between two genes, Endothelial Nitric Oxide Synthase and Notch1, would result in more severe types of congenital heart defects in animal models. Diabetes is known to be associated with decreased nitric oxide levels in blood vessels.
Maternal diabetes, in combination with a mutation in Notch1, would result in a higher risk of congenital heart disease.
Researchers showed that maternal hyperglycemia reduces the chromatin accessibility of the Endothelial Nitric Oxide Synthase gene, resulting in decreased nitric oxide production.
This loss of nitric oxide is associated with an increase in expression of Jarid2, a known repressor of the Notch1 gene. This directly inhibited Notch1 expression to levels below a critical threshold necessary for normal heart development. This study lends support to a gene-environment interaction model where maternal hyperglycemia raises the risk of congenital heart defects by reducing Notch1 expression.
The results reveal the epigenetic machinery by which maternal hyperglycemia disrupts the Nitric Oxide and Notch1 signaling pathways, leading to congenital heart defects. Infants that are exposed to hyperglycemia develop a congenital heart defect, which supports the idea that there are genetically susceptible individuals.
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