Electronic Thesis and Dissertation Repository

Degree

Doctor of Philosophy

Program

Physiology

Supervisor

Dr. Qingping Feng

Abstract

Women with pregestational diabetes are at a high risk of having babies with congenital heart defects (CHDs). The mechanisms of CHD induction in the offspring of women with pregestational diabetes remain elusive. With an ever-increasing rate of diabetes in young adults, there is a pressing need to understand the underlying mechanisms and initiate effective preventative strategies. The aim of this thesis is to study the role of reactive oxygen species (ROS) signalling in heart morphogenesis, unravel molecular mechanisms of CHDs induced by pregestational diabetes and provide new insights on potential therapeutic strategies. To this end, a mouse model of pregestational diabetes induced by streptozotocin was employed. A spectrum of septal, conotruncal and coronary artery malformation were identified in the offspring of mice with pregestational diabetes. Reactive oxygen species (ROS) levels were elevated and glutathione levels were diminished in the fetal hearts of diabetic female mice. Oral treatment with an antioxidant, N-Acetylcysteine (NAC), significantly diminished the incidence of CHDs and prevented coronary artery malformation in the offspring of pregestational diabetic mice. Furthermore, pregestational diabetes reduced cell proliferation, altered transcript levels, and disrupted epithelial to mesenchymal transition (EMT) in the fetal heart of pregestational diabetic mice, which were all prevented by NAC treatment. To further study the role of basal ROS production in embryonic heart development, a NADPH oxidase Nox2 knockout mouse was utilized. We demonstrated that loss of Nox2 expression decreased ROS production, and impaired TGF-β/BMP signalling and endocardial EMT in embryonic hearts. This ultimately resulted in cardiac septum and valve defects. Thus, under normal physiological conditions ROS production promotes heart development whereas excess ROS levels during pregestational diabetes induce CHDs. These studies show maintaining a balance of ROS levels is essential for normal embryonic heart development in mice. Furthermore, NAC may have a therapeutic potential in preventing the development of CHDs during pregestational diabetes.


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