Say NO to ROS: Their Roles in Embryonic Heart Development and Pathogenesis of Congenital Heart Defects in Maternal Diabetes

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.

Pathological Roles of Mitochondrial Oxidative Stress and Mitochondrial Dynamics in Cardiac Microvascular Ischemia/Reperfusion Injury

“…Then, glutathione peroxidase (GPX) catalyzes the reduction of H 2 O 2 into H 2 O through the oxidation of reduced glutathione (GSH) into its oxidized form (GSSG) [84,85]. Catalase in the mitochondrial matrix can also convert H 2 O 2 into water and molecular oxygen [86,87]. Glutathione biosynthesis is catalyzed by glutathione reductase using the oxidation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) into NADP and is crucial in antioxidant activities in the mitochondria [88,89] Another important source of ROS in the re-perfused heart are the two isoforms of monoamine oxidases (MAO), MAO-A and MAO-B, which are located on the outer mitochondrial membrane [92].…”

Association of Oxidative Stress on Pregnancy

“…Fetal exposure of a pregnant woman to heavy metals, such as lead and aluminum, has also been shown to be negative by disturbing the prooxidative-antioxidant balance. It is associated with an increase in MDA concentration and a decrease in the level of antioxidants such as superoxide dismutase (SOD) and glutathione peroxidase (GPx) in fetal cord blood serum with congenital heart disease [ 45 ].…”

Oxidative Stress and Vascular Dysfunction in the Retina: Therapeutic Strategies

“…Retinal vascular eNOS is essential for maintaining proper vascular function by generating NO. In this process, BH4 plays a key role in maintaining eNOS homodimer stabilization and binding of L-arginine to the active site [ 89 ]. However, some pathological conditions can cause a decrease in BH4 levels with a consecutive dysfunction of eNOS, also known as eNOS uncoupling.…”