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

Antioxidants ◽  
2019 ◽  
Vol 8 (10) ◽  
pp. 436 ◽  
Author(s):  
Engineer ◽  
Saiyin ◽  
Greco ◽  
Feng
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Embryonic Heart ◽  
Pregestational Diabetes ◽  
Enos Uncoupling

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.

scholarly journals Altered Inflow Hemodynamics affects Heart Development in a Side Specific Manner in the Embryonic Heart

2020 ◽  
Author(s):  
Maha W Alser ◽  
Huseyin Enes Salman ◽  
Huseyin Cagatay Yalcin
Keyword(s):  
Chick Embryo ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Heart Defects ◽  
Embryonic Heart ◽  
Cfd Analysis ◽  
Micro Ct ◽  
Left Heart ◽  
Right Heart

Background: Hemodynamics, forces from the flowing blood in the heart, is a major epigenetic factor for heart development. Disturbed hemodynamics were shown to induce cardiac malformations in the embryonic heart. Clinically relevant congenital heart defects (CHDs) can be introduced surgically in the lab by disturbing the hemodynamics, like Hypoplastic left heart syndrome (HLHS), characterized by underdeveloped left ventricle is underdeveloped. Left atrial ligation (LAL) on chick embryo is an experimental technique to produce a HLHS-like phenotype. Aims: To reveal mechanobiological mechanisms associated with disturbed hemodynamics that influence the progression of left ventricular hypoplasia using chick embryo model. We also introduce a new technique which we called right atrial ligation (RAL), to examine effect of flow disturbance in right heart. Methods: We combined multiple novel techniques in this research: Heart function was assessed via Echocardiography. Computational fluid dynamics (CFD) analysis was adapted for detailed hemodynamics assessment, such as wall shear stress and blood flow patterns. Heart morphology was assessed by histology, and micro-CT. Results: Echocardiography and CFD analysis showed flow and WSS levels decreased for the flow constricted side resulting in the flow diversion to the opposite side: LAL diverted flow to right side and RAL to left side. This disturbance resulted in underdevelopment of left heart (valve and ventricle) in LAL and underdevelopment of right heart in RAL, revealed with histology and micro-CT. Left side was affected more compared to right side, demonstrating higher plasticity in left heart. Conclusion: This study indicates the critical importance of altered inflow hemodynamics in cardiac development specifically valve and ventricle development. Our comprehensive approach can be used to predict the initiation and growth of congenital heart defects.

scholarly journals Sapropterin Treatment Prevents Congenital Heart Defects Induced by Pregestational Diabetes in Mice

2018 ◽  
Author(s):  
Anish Engineer ◽  
Tana Saiyin ◽  
Xiangru Lu ◽  
Andrew S. Kucey ◽  
Brad L. Urquhart ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Fetal Heart ◽  
Heart Defects ◽  
Lineage Tracing ◽  
Endocardial Cushions ◽  
Pregestational Diabetes ◽  
Diabetes In Mice ◽  
Enos Uncoupling

ABSTRACTAimsTetrahydrobiopterin (BH4) is a co-factor of endothelial nitric oxide synthase (eNOS), which is critical to embryonic heart development. We aimed to study the effects of sapropterin (Kuvan®), an orally active synthetic form of BH4 on eNOS uncoupling and congenital heart defects (CHDs) induced by pregestational diabetes in mice.MethodsAdult female mice were induced to pregestational diabetes by streptozotocin and bred with normal males to produce offspring. Pregnant mice were treated with sapropterin or vehicle during gestation. CHDs were identified by histological analysis. Cell proliferation, eNOS dimerization and reactive oxygen species (ROS) production were assessed in the fetal heart.ResultsPregestational diabetes results in a spectrum of CHDs in their offspring. Oral treatment with sapropterin in the diabetic dams significantly decreased the incidence of CHDs from 59% to 27% and major abnormalities, such as atrioventricular septal defect and double outlet right ventricle were absent in the sapropterin treated group. Lineage tracing reveals that pregestational diabetes results in decreased commitment of second heart field progenitors to the outflow tract, endocardial cushions, and ventricular myocardium of the fetal heart. Notably, decreased cell proliferation and cardiac transcription factor expression induced by maternal diabetes were normalized with sapropterin treatment. Furthermore, sapropterin administration in the diabetic dams increased eNOS dimerization and lowered ROS levels in the fetal heart.ConclusionsSapropterin treatment in the diabetic mothers improves eNOS coupling, increases cell proliferation and prevents the development of CHDs in the offspring. Thus, sapropterin may have therapeutic potential in preventing CHDs in pregestational diabetes.

scholarly journals Focused Strategies for Defining the Genetic Architecture of Congenital Heart Defects

Genes ◽  
2021 ◽  
Vol 12 (6) ◽  
pp. 827
Author(s):  
Lisa J. Martin ◽  
D Woodrow Benson
Keyword(s):  
Genetic Variation ◽  
Congenital Heart Defects ◽  
Heart Development ◽  
Genetic Architecture ◽  
Congenital Heart ◽  
Rare Variants ◽  
Heart Defects ◽  
Genetic Origin ◽  
Genetic Studies ◽  
The Ideal

Congenital heart defects (CHD) are malformations present at birth that occur during heart development. Increasing evidence supports a genetic origin of CHD, but in the process important challenges have been identified. This review begins with information about CHD and the importance of detailed phenotyping of study subjects. To facilitate appropriate genetic study design, we review DNA structure, genetic variation in the human genome and tools to identify the genetic variation of interest. Analytic approaches powered for both common and rare variants are assessed. While the ideal outcome of genetic studies is to identify variants that have a causal role, a more realistic goal for genetic analytics is to identify variants in specific genes that influence the occurrence of a phenotype and which provide keys to open biologic doors that inform how the genetic variants modulate heart development. It has never been truer that good genetic studies start with good planning. Continued progress in unraveling the genetic underpinnings of CHD will require multidisciplinary collaboration between geneticists, quantitative scientists, clinicians, and developmental biologists.

Abstract 650: Dose-response Effect of Hyperglycemia in Maternal Diabetes Mediated Congenital Heart Defects

2019 ◽  
Vol 125 (Suppl_1) ◽  
Author(s):  
Corrin Mansfield ◽  
Sathiyanarayanan Manivannan ◽  
Emily M Cameron ◽  
Vidu Garg ◽  
Madhumita Basu
Keyword(s):  
Congenital Heart Defects ◽  
Dose Response ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Response Effect ◽  
Dose Response Effect

Evaluation of oxidative stress in children with congenital heart defects

2011 ◽  
Vol 54 (1) ◽  
pp. 94-98 ◽  
Author(s):  
Ayfer Gözü Pirinccioglu ◽  
Ömer Alyan ◽  
Göksel Kizil ◽  
Murat Kangin ◽  
Nurcan Beyazit
Keyword(s):  
Oxidative Stress ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects

scholarly journals Semaphorin3f as an intrinsic regulator of chamber-specific heart development

2021 ◽  
Author(s):  
Rami Halabi ◽  
Paula B. Cechmanek ◽  
Carrie L. Hehr ◽  
Sarah McFarlane
Keyword(s):  
Congenital Heart Defects ◽  
Heart Development ◽  
Congenital Heart ◽  
Molecular Mechanisms ◽  
Heart Defects ◽  
Border Region ◽  
Specific Gene ◽  
Atrioventricular Canal ◽  
Term Survival ◽  
Ventricular Cardiomyocytes

During development a pool of precursors form a heart with atrial and ventricular chambers that exhibit distinct transcriptional and electrophysiological properties. Normal development of these chambers is essential for full term survival of the fetus, and deviations result in congenital heart defects. The large number of genes that may cause congenital heart defects when mutated, and the genetic variability and penetrance of the ensuing phenotypes, reveals a need to understand the molecular mechanisms that allow for the formation of chamber-specific cardiomyocyte differentiation. We find that in the developing zebrafish heart, mRNA for a secreted Semaphorin (Sema), Sema3fb, is expressed by all cardiomyocytes, whereas mRNA for its receptor Plexina3 (Plxna3) is expressed by ventricular cardiomyocytes. In sema3fb CRISPR zebrafish mutants, ventricular chamber development is impaired; the ventricles of mutants are smaller in size than their wild type siblings, apparently because of differences in cell size and not cell numbers, with ventricular cardiomyocytes failing to undergo normal developmental hypertrophy. Analysis of chamber differentiation indicates defects in chamber specific gene expression at the border between the ventricular and atrial chambers, with spillage of ventricular chamber genes into the atrium, and vice versa, and a failure to restrict bmp4a mRNA to the atrioventricular canal. The disrupted atrioventricular border region in mutants is accompanied by hypoplastic heart chambers and impaired cardiac function. These data suggest a model whereby cardiomyocytes secrete a Sema cue that, through spatially restricted expression of the receptor, signals in a ventricular chamber-specific manner to establish a distinct border between atrial and ventricular chambers that is important for functional development of the heart.

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