Poster abstracts
Poster number 56 submitted by Talita Choudhury
Impact Of Maternal Diabetes-associated Oxidative Stress On The Developing Endocardium
Talita Z Choudhury (Molecular, Cellular, Developmental Biology Graduate Program, The Ohio State University), Sarah Greskovich (Department of Molecular Genetics, The Ohio State University), Emily Morris Cameron (Center for Cardiovascular Research, Nationwide Childrens Hospital), Holly Girard (Center for Cardiovascular Research, Nationwide Childrens Hospital), Sara Adamczak (Center for Cardiovascular Research, Nationwide Childrens Hospital), Vidu Garg (Center for Cardiovascular Research, Nationwide Childrens Hospital)
Abstract:
Congenital heart defects (CHD) affect 1% of all live births and are the leading cause of birth defect-related mortality. The etiology of CHD is multifactorial as genomic variation and environmental factors act as contributors. Among the environmental teratogens, maternal pre-gestational diabetes mellitus and its concurrent maternal hyperglycemia (matHG) is associated with a ~5-fold increased risk of CHD. Oxidative stress (Ox-Stress) due to generation of excess reactive oxygen species is observed in embryonic hearts exposed to matHG in animal models, but the teratogenic effect of excess Ox-stress on cardiac development has not been fully elucidated. Previously, we reported a gene-environment (GxE) interaction between matHG and Notch1 haploinsufficiency resulting in CHD in mice. Here, we hypothesize that matHG-induced Ox-Stress leads to aberrant endocardial cell (EC) function via abnormal Notch signaling leading to CHD. Preliminary results show mouse embryos exposed to matHG with conditional haploinsufficiency of endocardial Notch1 have highly penetrant CHD. We found increased Ox-Stress in EC-derived endocardial cushions of both wildtype and Notch1+/- embryos. Lineage tracing of EC revealed reduced number of EC-derived mesenchymal cells in endocardial cushions of matHG exposed embryos compared to non-MatHG embryos and investigations between wildtype and Notch1+/- embryos are ongoing. Interestingly, modulating intracellular levels of oxidative stress via overexpression of antioxidant enzyme, SOD1, reduced the incidence of CHD in SOD1+ embryos compared to wildtype littermates but not SOD1+;Notch1+/- compared to Notch1+/- littermates exposed to matHG. This work shows matHG-induced Ox-Stress may be associated with aberrant EC and EC-derived cell functions and mitigating matHG-induced Ox-Stress reduces the incidence of CHD in wildtype mice. Additionally, our results suggest therapeutic antioxidant strategies to mitigate matHG-associated CHD may not be applicable in presence of a genetic modifier such as Notch1.
Keywords: congenital heart defects, Oxidative stress, Notch1 signaling