Poster abstracts
Poster number 43 submitted by Talita Choudhury
Role of reactive oxygen species in maternal hyperglycemia-induced congenital heart defects: a potential therapeutic target
Talita Choudhury (Center for Cardiovascular Research, Nationwide Childrens Hospital, Columbus, OH ), Sara Adamczak (Center for Cardiovascular Research, Nationwide Childrens Hospital, Columbus, OH ), Emily Morris Cameron (Center for Cardiovascular Research, Nationwide Childrens Hospital, Columbus, OH ), Madhumita Basu (Center for Cardiovascular Research, Nationwide Childrens Hospital, Columbus, OH ), Vidu Garg (Center for Cardiovascular Research, Nationwide Childrens Hospital, Columbus, OH )
Abstract:
Congenital heart defects (CHD) affect 1% of all live births in the US annually. The etiology of CHD is multifactorial, that is, both pathogenic genomic variation and environmental risk factors act as CHD contributors. Among the environmental teratogens, maternal pre-gestational diabetes mellitus (matDM) is associated with up to ~5-fold increase in the risk of having an infant with CHD. Generation of excess reactive oxygen species (ROS) due to maternal hyperglycemia is routinely observed in embryonic hearts exposed to matDM but the teratogenic effect of ROS on cardiac developmental pathways is not fully understood. The Notch and Nitric oxide (NO) signaling pathways, which are highly expressed in the endocardium, are critical for normal heart development. Previously, we identified a reduction in NO bioavailability and Notch signaling in mouse embryonic hearts exposed to matDM and reported a gene-environment interaction between Notch1+/- and matDM in the development of CHD. Here, we investigated the effect of modulating intracellular levels of oxidative stress in endocardial and endocardial-derived cell lineages to determine the role of ROS in matDM-associated CHD. Endocardial-derived cells exposed to oxidative stress elicit similar responses as hyperglycemia in reduction of NO bioavailability and Notch signaling. To study the role of oxidative stress in vivo, we generated WT and Notch1+/- embryos overexpressing the antioxidant gene, SOD1, to determine whether mitigating oxidative stress can rescue matDM associated CHD. We have confirmed a reduction of oxidative stress in SOD1-tg embryonic hearts and preliminary data shows lower incidence of CHD in SOD1-tg compared to WT embryos exposed to matDM. The role of oxidative stress in matDM-associated CHD requires further investigation, as mitigation of endocardial oxidative stress may be a promising approach to lower the incidence of CHD in high-risk populations.
References:
Basu M, Zhu JY, LaHaye S, Majumdar U, Jiao K, Han Z, Garg V. Epigenetic mechanisms underlying maternal diabetes-associated risk of congenital heart disease. JCI insight. 2017 Oct 19;2(20).
Keywords: congenital heart defects, maternal diabetes, oxidative stress