Poster abstracts
Poster number 50 submitted by Talita Choudhury
Elucidating mechanisms underlying maternal hyperglycemia induced congenital heart defects
Talita Choudhury (Molecular, Cellular, Developmental Biology Graduate Program, The Ohio State University), Emily M. Cameron (Heart Center, Nationwide Childrens Hospital), Sara Adamczak (Heart Center, Nationwide Childrens Hospital), Uddalak Majumdar (Heart Center, Nationwide Childrens Hospital), Madhumita Basu (Heart Center, Nationwide Childrens Hospital), Vidu Garg (Heart Center, Nationwide Childrens Hospital)
Abstract:
Congenital heart defects (CHD) affect 1% of live births in the US each year. Both genetic and environmental contributors play a role in the development of CHD and most cases are proposed to be a result of complex gene-environment interactions that disrupt cardiac morphogenesis in utero. Among the risk factors for CHD, maternal pre-gestational diabetes mellitus is associated with up to a 5-fold increase in the risk of having an infant with CHD. Maternal diabetes disrupts several fetal cardiac developmental pathways including those that regulate endocardial cushion development such as Nitric Oxide (NO) and Notch signaling. Furthermore, Notch1+/- mouse embryos exposed to maternal diabetes have highly penetrant CHD phenotypes. Excess reactive oxygen species due to hyperglycemia has been proposed to be a critical driver for the cardiovascular effects of diabetes mellitus. In this study, we investigated the effect of hyperglycemia and increasing levels of oxidative stress on endothelial nitric oxide synthase (NOS3) and Notch signaling during cardiac development. In vitro studies showed reduced NO bioavailability under hyperglycemia and oxidative stress conditions compared to normoglycemia. Reduced NO bioavailability with increased oxidative stress was also observed in embryos exposed to maternal diabetes compared to non-diabetic embryos. In order to study the role of oxidative stress and Notch signaling in vivo, the antioxidant enzyme SOD1 was overexpressed in murine embryos from diabetic pregnancies to determine if SOD1 could reduce oxidative stress and rescue the CHD phenotypes. We generated SOD1+, SOD1+;Notch1+/-, WT and Notch1+/- embryos exposed to maternal diabetes and found reduced incidence of CHD in SOD1+ embryos from diabetic pregnancies compared to WT littermates. The role of oxidative stress in maternal diabetes mediated congenital heart defects requires further investigation and mitigation of oxidative stress may be a promising approach to lower the incidence of CHD from maternal diabetes exposure.
Keywords: maternal diabetes, oxidative stress, Notch signaling