Electronic Thesis and Dissertation Repository

Thesis Format

Integrated Article

Degree

Doctor of Philosophy

Program

Physiology and Pharmacology

Collaborative Specialization

Developmental Biology

Supervisor

Feng, Qingping

Abstract

Congenital heart defects (CHDs) arise from perturbations in complex molecular and cellular processes underlying normal embryonic heart development. CHDs are the most common congenital malformation, occurring in 1 to 5% of live births, and are the leading cause of pediatric mortality. Adverse genetic and environmental factors can impede normal cardiogenesis and increase the likelihood of CHDs. Pregestational maternal diabetes increases the risk of CHDs in children by more than four-fold. As the prevalence of diabetes rapidly rises among women of childbearing age, there is a need to investigate the mechanisms and potential preventative strategies for these defects. The aim of this thesis was to explore the pathogenesis of pregestational diabetes-induced CHDs and coronary artery malformations (CAMs), while testing the efficacy of two clinically relevant pharmacotherapies. To this end, using a mouse model of pregestational diabetes, I examined the impact of hyperglycemia-induced elevations in oxidative stress and miR-122 on heart development, concurrently determining the preventative capabilities of sapropterin or antimiR-122 treatment. I confirmed that pregestational diabetes results in spectrum of CHDs, CAMs and cardiac function deficits, and that their incidence is significantly lowered with either sapropterin or antimiR-122. Specifically, sapropterin treatment lowered the incidence of CHDs and CAMs from 59% and 50% to 27% and 21%, respectively. Similarly, antimiR-122 therapy reduced this incidence of CHDs from 57% to 23%. These morphological malformations range in severity, and include septal and outflow defects (OFT), myocardium deficiencies, and hypoplastic coronary arteries. Lineage tracing experiments revealed a diminished commitment of second heart field progenitors to the OFT, endocardial cushions and ventricular myocardium in embryonic hearts from diabetic dams. In addition, deficits in cardiogenic gene expression, enzyme activity, cell proliferation, and epicardial EMT, induced by pregestational diabetes, contribute to these defects, and were prevented by both treatments. Specifically, sapropterin treatment reestablished the functional eNOS dimer and restored its phosphorylation in embryonic hearts of diabetic dams, leading to normal cardiovascular development. Conversely, antimiR-122 attenuated the targeting and inhibition of key genes responsible for cardiogenesis by miR-122. These results suggest that sapropterin and antimiR-122 may have therapeutic potential in preventing CHDs in children of women with pregestational diabetes.

Summary for Lay Audience

The most common birth defects are congenital malformations of the heart, accounting for 1-5% of live births. Newborns with congenital heart defects have an increased risk of mortality, as proper function of the heart is compromised when specific development is not attained during gestation. Congenital heart defects can go unnoticed by doctors at birth, however, as the child matures and is involved in increasing amounts of physical activity, the congenital malformations can manifest themselves. Therefore, it is vital that research be conducted into how and why these malformations develop, and more significantly, what remedies during pregnancy can prevent their occurrence. In terms of how these defects arise, it has been previously shown that pregestational diabetes in the mother increases the risk for congenital heart defects in the child by over 50%. Studies in animal models have confirmed diabetes as a risk factor for newborns with malformed hearts. This connection is alarming as the incidence of diabetes in a younger demographic is seemingly increasing. This is also true for the female population, specifically in North America. More and more women are being diagnosed as diabetic at a younger age, and if these women have children, their offspring may have a serious, life-threatening medical condition. Therefore, it is beneficial not only to the lives of these children, but also to the health-care system to find a solution to this problem. This research will attempt to do just that, as we will investigate whether administration of sapropterin or antimiR-122 will decrease the presence of heart defects in the offspring of diabetic mouse mothers.

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