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

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 Abnormal Expression of MST1 and YAP1 in Fetal Heart Tissue in a Hyperglycemic Environment and Their Roles in Mediating Apoptosis

2020 ◽  
Author(s):  
Dongmei Su ◽  
Yanhua Li ◽  
Lina Guan ◽  
Qian Li ◽  
Cuige Shi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Western Blot ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Cardiomyocyte Apoptosis ◽  
Induced Apoptosis

Abstract Background：Gestational diabetes mellitus is a risk factor for congenital heart defects. The article aimed to investigate the expression and roles of Mst1, Yap1, Last1/2 and Survivin in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced heart abnormality. Methods：The gene and protein expression were assessed by quantitative PCR, western blot, and immunohistochemical staining. The protein phosphorylation level were analyzed by western blot .Knockdown of gene expression were assessed by RNA interference. Hoechst 33342 staining assay were performed to explore H9C2 apoptosis. Diabetes mellitus was induced in rats using streptozotocin.Results：Our results revealed that increased MST1 protein levels in the heart tissues of the offspring of diabetic rats in vivo occurred concomitantly with HG-induced apoptosis in H9C2 cardiomyocytes in vitro. Knockdown and overexpression experiments showed that MST1 played a key role in mediating HG-induced apoptosis in cardiomyocytes. Downregulation of YAP1 was associated with HG-induced, MST1-mediated cardiomyocyte apoptosis. Further study showed that MST1 downregulated the protein level of YAP1 through mediation of YAP1 phosphorylation on Ser127 and Ser397; this process also required LATS1/2 participation. MST1 overexpression increased the phosphorylation levels of LATS1/2, which were also shown to be increased in the heart tissues of diabetic offspring. We also found that YAP1 mediated the expression of Survivin during HG-induced apoptosis, and the Survivin-inhibitor YM155 partially inhibited the role of YAP1 in suppressing apoptosis induced by HG in cardiomyocytes. Conclusion：These findings reveal a regulatory mechanism of MST1/YAP1/Survivin signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.

scholarly journals Blood flow patterns underlie developmental heart defects

2017 ◽  
Vol 312 (3) ◽  
pp. H632-H642 ◽  
Author(s):  
Madeline Midgett ◽  
Kent Thornburg ◽  
Sandra Rugonyi
Keyword(s):  
Blood Flow ◽  
Congenital Heart Defects ◽  
Dose Response ◽  
Congenital Heart ◽  
Heart Defects ◽  
Flow Patterns ◽  
Early Embryo ◽  
Response Type ◽  
Cardiac Defects ◽  
Blood Flow Patterns

Although cardiac malformations at birth are typically associated with genetic anomalies, blood flow dynamics also play a crucial role in heart formation. However, the relationship between blood flow patterns in the early embryo and later cardiovascular malformation has not been determined. We used the chicken embryo model to quantify the extent to which anomalous blood flow patterns predict cardiac defects that resemble those in humans and found that restricting either the inflow to the heart or the outflow led to reproducible abnormalities with a dose-response type relationship between blood flow stimuli and the expression of cardiac phenotypes. Constricting the outflow tract by 10–35% led predominantly to ventricular septal defects, whereas constricting by 35–60% most often led to double outlet right ventricle. Ligation of the vitelline vein caused mostly pharyngeal arch artery malformations. We show that both cardiac inflow reduction and graded outflow constriction strongly influence the development of specific and persistent abnormal cardiac structure and function. Moreover, the hemodynamic-associated cardiac defects recapitulate those caused by genetic disorders. Thus our data demonstrate the importance of investigating embryonic blood flow conditions to understand the root causes of congenital heart disease as a prerequisite to future prevention and treatment. NEW & NOTEWORTHY Congenital heart defects result from genetic anomalies, teratogen exposure, and altered blood flow during embryonic development. We show here a novel “dose-response” type relationship between the level of blood flow alteration and manifestation of specific cardiac phenotypes. We speculate that abnormal blood flow may frequently underlie congenital heart defects.

scholarly journals Selected environmental risk factors and congenital heart defects

Medicina ◽  
2008 ◽  
Vol 44 (11) ◽  
pp. 827 ◽  
Author(s):  
Renata Kučienė ◽  
Virginija Dulskienė
Keyword(s):  
Risk Factors ◽  
Congenital Heart Defects ◽  
Environmental Risk ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Epidemiological Studies ◽  
Environmental Risk Factors ◽  
Congenital Heart Malformations ◽  
Genetic And Environmental Factors

The aim of the article is to review the published scientific literature and epidemiological studies about the effect of selected environmental risk factors on congenital heart defects in infants. According to recent reports, the prevalence of congenital heart defects is around 1% of live births. Congenital heart malformations are the leading cause of infant mortality. Unfortunately, the majority of the causes of heart defects remain unknown. These malformations are caused by interaction of genetic and environmental factors. The article reviews selected environmental risk factors: maternal illnesses and conditions associated with metabolic disorder (maternal diabetes, obesity, phenylketonuria), maternal lifestyle factors (alcohol use, smoking), which may increase the risk of congenital heart defects.

scholarly journals Elevated MST1 leads to apoptosis via depletion of YAP1 in cardiomyocytes exposed to high glucose

2021 ◽  
Vol 27 (1) ◽  
Author(s):  
Dongmei Su ◽  
Yanhua Li ◽  
Lina Guan ◽  
Qian Li ◽  
Cuige Shi ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Western Blot ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes ◽  
Cardiomyocyte Apoptosis ◽  
Induced Apoptosis

Abstract Background Gestational diabetes mellitus is a risk factor for congenital heart defects. The article aimed to investigate the expression and roles of MST1, YAP1, Last1/2 and Survivin in modulating HG-induced cardiomyocyte apoptosis and maternal diabetes-induced heart abnormality. Methods Diabetes mellitus was induced in rats using streptozotocin. The protein expression and phosphorylation analysis in fetal heart tissue was assessed by western blot and immunohistochemical staining. Hoechst 33342 staining assay was performed to explore H9C2 apoptosis. The gene and protein expression in H9C2 cells was assessed by quantitative PCR and western blot. Knockdown of gene expression was assessed by RNA interference. Results Our results revealed that increased MST1 protein levels in the heart tissues of the offspring of diabetic rats in vivo and in H9C2 cardiomyocytes under HG treatment in vitro, respectively. Knockdown and overexpression experiments showed that MST1 played a key role in mediating HG-induced apoptosis in cardiomyocytes. Downregulation of YAP1 was associated with HG-induced, MST1-mediated cardiomyocyte apoptosis. Further study showed that MST1 downregulated the protein level of YAP1 through mediation of YAP1 phosphorylation on Ser127 and Ser397; this process also required LATS1/2 participation. MST1 overexpression increased the phosphorylation levels of LATS1/2, which were also shown to be increased in the heart tissues of diabetic offspring. We also found that YAP1 mediated the expression of Survivin during HG-induced apoptosis, and the Survivin-inhibitor YM155 partially inhibited the role of YAP1 in suppressing apoptosis induced by HG in cardiomyocytes. Conclusion These findings reveal a regulatory mechanism of MST1/YAP1/Survivin signaling in modulating cardiomyocyte apoptosis in vitro and maternal diabetes-induced congenital heart defects in vivo.

Maternal Diabetes, Birth Weight, and Neonatal Risk of Congenital Heart Defects in Norway, 1994–2009

2016 ◽  
Vol 128 (5) ◽  
pp. 1116-1125 ◽  
Author(s):  
Elisabeth Leirgul ◽  
Kristoffer Brodwall ◽  
Gottfried Greve ◽  
Stein E. Vollset ◽  
Henrik Holmstrøm ◽  
...  
Keyword(s):  
Birth Weight ◽  
Congenital Heart Defects ◽  
Congenital Heart ◽  
Heart Defects ◽  
Maternal Diabetes

scholarly journals Maternal Body Mass Index and Risk of Congenital Heart Defects in Infants: A Dose-Response Meta-Analysis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Xuezhen Liu ◽  
Guoyong Ding ◽  
Weili Yang ◽  
Xia Feng ◽  
Yuejin Li ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Body Mass ◽  
Congenital Heart Defects ◽  
Dose Response ◽  
Congenital Heart ◽  
Heart Defects ◽  
Meta Analysis ◽  
Maternal Body Mass Index ◽  
Increased Risk ◽  
Maternal Bmi

Objective. The exact shape of the dose-response relationship between maternal body mass index (BMI) and the risk of congenital heart defects (CHDs) in infants has not been clearly defined yet. This study aims to further clarify the relationship between maternal obesity and the risk of CHDs in infants by an overall and dose-response meta-analysis. Methods. PubMed, Embase, and Web of Science databases were searched to identify all related studies. The studies were limited to human cohort or case-control studies in English language. Random-effect models and dose-response meta-analysis were used to synthesize the results. Heterogeneity, subgroup analysis, sensitivity analysis, and publication bias were also assessed. Results. Nineteen studies with 2,416,546 participants were included in our meta-analysis. Compared with the mothers with normal weight, the pooled relative risks (RRs) of infants with CHDs were 1.08 (95% CI=1.03-1.13) in overweight and 1.23 (95% CI=1.17-1.29) in obese mothers. According to the findings from the linear meta-analysis, we observed an increased risk of infants with CHDs (RR=1.07, 95% CI=1.06-1.08) for each 5 kg/m2 increase in maternal BMI. A nonlinear relationship between maternal BMI and risk of infants with CHDs was also found (p=0.012). Conclusion. The results from our meta-analysis indicate that increased maternal BMI is related to increased risk of CHDs in infants.

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