The Role of Maternal Diabetes and Notch1 on the Development of Congenital Heart Disease
Ryan Koch
Introduction. Congenital heart disease (CHD) is when there is a defect in a heart wall, valve, or blood vessel from birth. CHD is the most common birth defect in the world involving one percent of births and ten percent of stillborns1,2. Only 20-30% of CHD cases have been linked to genetic causes2. Treatment has remained largely unchanged for decades, commonly consisting of invasive surgery or palliative care1,2. Epigenetic modifications or mutations in Notch1 have commonly been associated with CHD3. Maternal diabetes has been linked to higher rates on CHD4; however, the mechanism has remained largely elusive. This mini review analyzes what is currently known of this mechanism. Methods. 30 million live births in the United States were analyzed for congenital anomalies including cyanotic CHD from mothers with diabetes. Immortalized atrioventricular cushion mesenchymal cells were grown in hyperglycemic conditions and levels of NO, ROS, Jarid2, and Notch1 were measured throughout6. Female mice were injected with streptozotocin, a toxin which induced diabetes, and mated6,7,8. Some pregnant mice were then given a running wheel to exercise, while others were not given a means of exercising. A gross observation of fetal hearts and an analysis of ROS and Notch1 levels were performed on day E18.57. A new group of diabetic pregnant mice were given sapropterin, a synthetic form of tetrahydrobiopterin (BH4). Gross observation of fetal hearts and an analysis of eNOS dimers and NO levels was performed8. Results. Babies born to mothers with pre-pregnancy diabetes and gestational diabetes were at a 5.07 and 1.52 higher rate of developing CHD respectively5. Cells grown in hyperglycemic conditions had decreased NO production and Notch1 expression while having increased expression of Jarid2 and ROS production6. Exercise lowered CHD incidence from 56.8% to 25%, lowered ROS levels, and restored normal Notch1 levels7. Likewise, sapropterin reduced CHD incidence from 59.4% to 26.5%, of which, many of the offspring had less severe defects. An increase in eNOS dimerization levels and in the right and left heart ventricular walls thickness were also observed8. Conclusions. Hyperglycemic conditions caused cells to have decreased chromatin accessibility at Nos3, leading to a decreased NO production and increased ROS production. The lower levels of NO led to increased Jarid2 expression, which in turn, lowered Notch1. Notch1 subsequently dropped below a threshold and caused the development of CHD6. Maternal exercise and Sapropterin supplementation may be possible treatments to counteract this mechanism and prevent CHD caused by maternal diabetes7,8.
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