Nitric Oxide Synthase-3 Promotes Embryonic Development of Atrioventricular Valves

Yin, Long; Lu, Xiangru; Xiang, Fu-Li; Lu, Mengji; Feng, Qingping

doi:10.1371/journal.pone.0077611

Cited by 20 publications

(17 citation statements)

References 42 publications

(53 reference statements)

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“…Primer sequences are shown in Table . The mRNA levels in relation to 28S ribosomal RNA were determined using a comparative C T method …”

Section: Methodsmentioning

confidence: 99%

Rac1 Signaling Is Critical to Cardiomyocyte Polarity and Embryonic Heart Development

Leung

Liu

et al. 2014

JAHA

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BackgroundDefects in cardiac septation are the most common form of congenital heart disease, but the mechanisms underlying these defects are still poorly understood. The small GTPase Rac1 is implicated in planar cell polarity of epithelial cells in Drosophila; however, its role in mammalian cardiomyocyte polarity is not clear. We tested the hypothesis that Rac1 signaling in the second heart field regulates cardiomyocyte polarity, chamber septation, and right ventricle development during embryonic heart development.Methods and ResultsMice with second heart field–specific deficiency of Rac1 (Rac1SHF) exhibited ventricular and atrial septal defects, a thinner right ventricle myocardium, and a bifid cardiac apex. Fate‐mapping analysis showed that second heart field contribution to the interventricular septum and right ventricle was deficient in Rac1SHF hearts. Notably, cardiomyocytes had a spherical shape with disrupted F‐actin filaments in Rac1SHF compared with elongated and well‐aligned cardiomyocytes in littermate controls. Expression of Scrib, a core protein in planar cell polarity, was lost in Rac1SHF hearts with decreased expression of WAVE and Arp2/3, leading to decreased migratory ability. In addition, Rac1‐deficient neonatal cardiomyocytes displayed defects in cell projections, lamellipodia formation, and cell elongation. Furthermore, apoptosis was increased and the expression of Gata4, Tbx5, Nkx2.5, and Hand2 transcription factors was decreased in the Rac1SHF right ventricle myocardium.ConclusionsDeficiency of Rac1 in the second heart field impairs elongation and cytoskeleton organization of cardiomyocytes and results in congenital septal defects, thin right ventricle myocardium, and a bifid cardiac apex. Our study suggests that Rac1 signaling is critical to cardiomyocyte polarity and embryonic heart development.

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“…Primer sequences are shown in Table . The mRNA levels in relation to 28S ribosomal RNA were determined using a comparative C T method …”

Section: Methodsmentioning

confidence: 99%

Rac1 Signaling Is Critical to Cardiomyocyte Polarity and Embryonic Heart Development

Leung

Liu

et al. 2014

JAHA

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“…Ventricles of E12.5 embryos from control dams were harvested and cultured on collagen gel (25). Collagen (1 mg/mL, type I collagen of rat's tail; BD Bioscience) was prepared in M199 media (M5017; Sigma) containing 5 mmol/L D-glucose or in M199 media with an additional 25 mmol/L D-glucose, making the final D-glucose concentration 30 mmol/L.…”

Section: Ex Vivo Heart Explant Culturementioning

confidence: 99%

“…Samples were amplified for 35 cycles using Eppendorf realplex (Eppendorf, Hamburg, Germany). The mRNA levels in relation to 28S rRNA were determined (25).…”

Section: Real-time Rt-pcrmentioning

confidence: 99%

Pregestational Diabetes Induces Fetal Coronary Artery Malformation via Reactive Oxygen Species Signaling

Moazzen

Liu

et al. 2014

Diabetes

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Hypoplastic coronary artery disease is a congenital coronary artery malformation associated with a high risk of sudden cardiac death. However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Pregestational diabetes increases reactive oxygen species (ROS) levels and the risk of congenital heart defects. We show that pregestational diabetes in mice induced by streptozotocin significantly increased 4-hydroxynonenal production and decreased coronary artery volume in fetal hearts. Pregestational diabetes also impaired epicardial epithelialto-mesenchymal transition (EMT) as shown by analyses of the epicardium, epicardial-derived cells, and fate mapping. Additionally, the expression of hypoxia-inducible factor 1a (Hif-1a), Snail1, Slug, basic fibroblast growth factor (bFgf), and retinaldehyde dehydrogenase (Aldh1a2) was decreased and E-cadherin expression was increased in the hearts of fetuses of diabetic mothers. Of note, these abnormalities were all rescued by treatment with N-acetylcysteine (NAC) in diabetic females during gestation. Ex vivo analysis showed that high glucose levels inhibited epicardial EMT, which was reversed by NAC treatment. We conclude that pregestational diabetes in mice can cause coronary artery malformation through ROS signaling. This study may provide a rationale for further clinical studies to investigate whether pregestational diabetes could cause hypoplastic coronary artery disease in humans.Pregestational diabetes is a risk factor for congenital heart defects in infants (1,2). Clinical studies have shown that pregestational diabetes increases the risk of congenital heart defects in the offspring by three-to fivefold compared with nondiabetic pregnancies (1-3). To date, analysis of congenital heart malformation in the newborn is mainly restricted to major cardiac structures, which include the aorta, pulmonary artery, atrioventricular septum, cardiac valves, and myocardium, but coronary arteries are not routinely examined (4). Congenital malformation can occur in the coronary arteries, leading to null coronary artery or hypoplastic coronary artery disease (5). Although null coronary artery is embryonically lethal, hypoplastic coronary artery disease is a rare congenital coronary abnormality defined by malformation of one or more major branches of the coronary arteries with a marked decrease in luminal diameter and length. Hypoplastic coronary artery disease can be asymptomatic but often is associated with myocardial infarction and sudden cardiac death during intense physical activity (6). However, the etiology and pathogenesis of hypoplastic coronary artery disease remain undefined. Furthermore, it is not known whether pregestational diabetes results in coronary artery malformation in offspring. Isolated cases of congenital coronary artery abnormalities have been identified in infants by autopsy. However, whether the mothers of these infants had pregestational diabetes was not disclosed in these reports (7,8). A large multicenter case-control study sho...

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“…Similar to vascular endothelial cells, VECs also require NO to maintain function as reduced bioavailability of endothelium-derived NO leads to morphological defects at birth and dysfunction in adults. (4, 16, 22–25) While the requirement for NO is conserved, previous studies have noted several differences between vascular and valvular endothelial cells largely in their molecular and phenotypic response to biomechanical stress. (26) Therefore it is not clear if determinants of age-related endothelial cell dysfunction in vascular disease can account for failure of the valve to maintain structure-function relationships later in life.…”

Section: Introductionmentioning

confidence: 99%

Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation

Anstine

Bobba

Ghadiali

et al. 2016

Journal of Molecular and Cellular Cardiology

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Risk factors of heart valve disease are well defined and prolonged exposure throughout life leads to degeneration and dysfunction in up to 33% of the population. While aortic valve replacement remains the most common need for cardiovascular surgery particularly in those aged over 65, the underlying mechanisms of progressive deterioration are unknown. In other cardiovascular systems, a decline in endothelial cell integrity and function play a major role in promoting pathological changes, and while similar mechanisms have been speculated in the valves, studies to support this are lacking. The goal of this study was to examine age-related changes in valve endothelial cell (VEC) distribution, morphology, function and transcriptomes during critical stages of valve development (embryonic), growth (post natal (PN)), maintenance (young adult) and aging (aging adult). Using a combination of in vivo mouse, and in vitro porcine assays we show that VEC function including, nitric oxide bioavailability, metabolism, endothelial-to-mesenchymal potential, membrane self repair and proliferation decline with age. In addition, density of VEC distribution along the endothelium decreases and this is associated with changes in morphology, decreased cell-cell interactions, and increased permeability. These changes are supported by RNA-seq analysis showing that focal adhesion-, cell cycle-, and oxidative phosphorylation-associated biological processes are negatively impacted by aging. Furthermore, by performing high-throughput analysis we are able to report the differential and common transcriptomes of VECs at each time point that can provide insights into the mechanisms underlying age-related dysfunction. These studies suggest that maturation of heart valves over time is a multifactorial process and this study has identified several key parameters that may contribute to impairment of the valve to maintain critical structure-function relationships; leading to degeneration and disease.

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Nitric Oxide Synthase-3 Promotes Embryonic Development of Atrioventricular Valves

Cited by 20 publications

References 42 publications

Rac1 Signaling Is Critical to Cardiomyocyte Polarity and Embryonic Heart Development

Rac1 Signaling Is Critical to Cardiomyocyte Polarity and Embryonic Heart Development

Pregestational Diabetes Induces Fetal Coronary Artery Malformation via Reactive Oxygen Species Signaling

Growth and maturation of heart valves leads to changes in endothelial cell distribution, impaired function, decreased metabolism and reduced cell proliferation

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