Abstract
Congenital heart defects (CHDs) are the most prevalent and serious birth defect, occurring in 1% of all live births. Pregestational maternal diabetes is a known risk factor for the development of CHDs, elevating the risk in the child 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. In experimental animal models of pregestational diabetes induced-CHDs, upwards of 50% of offspring display congenital malformations of the heart, including septal, valvular, and outflow tract defects. Specifically, the imbalance of nitric oxide (NO) and reactive oxygen species (ROS) signaling is a major driver of the development of CHDs in offspring of mice with pregestational diabetes. NO from endothelial nitric oxide synthase (eNOS) is crucial to cardiogenesis, regulating various cellular and molecular processes. In fact, deficiency in eNOS results in CHDs and coronary artery malformation. Embryonic hearts from diabetic dams exhibit eNOS uncoupling and oxidative stress. Maternal treatment with sapropterin, a cofactor of eNOS, and antioxidants such as N-acetylcysteine, vitamin E, and glutathione as well as maternal exercise have been shown to improve eNOS function, reduce oxidative stress, and lower the incidence CHDs in the offspring of mice with pregestational diabetes. This review summarizes recent data on pregestational diabetes-induced CHDs, and offers insights into the important roles of NO and ROS in embryonic heart development and pathogenesis of CHDs in maternal diabetes.
Highlights
Congenital heart defects (CHDs) are the most common structural birth defect, occurring in 1–5%of live births [1,2,3]
The teratogenic potential of maternal hyperglycemia has been well documented for generations, and research far has uncovered perturbations to reactive oxygen species (ROS) and nitric oxide (NO) homeostasis to be major drivers of this phenomenon
Cardiogenesis is a highly complex process governed by a multitude of factors that are sensitive to oxidative damage, including endothelial nitric oxide synthase (eNOS), the enzyme that produces
Summary
Congenital heart defects (CHDs) are the most common structural birth defect, occurring in 1–5%. A common, established method for the generation of a type 1 diabetes (T1D) model in rodents is streptozotocin (STZ) administration [10,11]. This chemical agent is a glucose analogue, which is taken up by pancreatic β-cells via the glucose transporter 2. Animal studies analyzing heart development in this model of pregestational maternal diabetes indicate that reactive oxygen species (ROS) are critical players in mediating maladaptive heart development, leading to CHDs [13,14,15,16,17,18,19,20,21,22,23,24,25]. We examine the etiology and epidemiology of pregestational diabetes-induced CHDs and summarize numerous rodent studies looking at this link, while focusing on the pathophysiological role of ROS and eNOS uncoupling
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