scholarly journals Gata4 drives Hh-signaling for second heart field migration and outflow tract development

2018 ◽  
Author(s):  
Jielin Liu ◽  
Henghui Cheng ◽  
Menglan Xiang ◽  
Lun Zhou ◽  
Ke Zhang ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Right Ventricle ◽  
Double Outlet Right Ventricle ◽  
Precursor Cells ◽  
Outflow Tract ◽  
Second Heart Field ◽  
Heart Field ◽  
Hh Signaling ◽  
The Right ◽  
Cardiac Precursor Cells

AbstractDominant mutations of Gata4, an essential cardiogenic transcription factor (TF), cause outflow tract (OFT) defects in both human and mouse. We investigated the molecular mechanism underlying this requirement. Gata4 happloinsufficiency in mice caused OFT defects including double outlet right ventricle (DORV) and conal ventricular septum defects (VSDs). We found that Gata4 is required within Hedgehog (Hh)-receiving second heart field (SHF) progenitors for normal OFT alignment. Increased Pten-mediated cell-cycle transition, rescued atrial septal defects but not OFT defects in Gata4 heterozygotes. SHF Hh-receiving cells failed to migrate properly into the proximal OFT cushion in Gata4 heterozygote embryos. We find that Hh signaling and Gata4 genetically interact for OFT development. Gata4 and Smo double heterozygotes displayed more severe OFT abnormalities including persistent truncus arteriosus (PTA) whereas restoration of Hedgehog signaling rescued OFT defects in Gata4-mutant mice. In addition, enhanced expression of the Gata6 was observed in the SHF of the Gata4 heterozygotes. These results suggested a SHF regulatory network comprising of Gata4, Gata6 and Hh-signaling for OFT development. This study indicates that Gata4 potentiation of Hh signaling is a general feature of Gata4-mediated cardiac morphogenesis and provides a model for the molecular basis of CHD caused by dominant transcription factor mutations.Author SummaryGata4 is an important protein that controls the development of the heart. Human who possess a single copy of Gata4 mutation display congenital heart defects (CHD), including the double outlet right ventricle (DORV). DORV is an alignment problem in which both the Aorta and Pulmonary Artery originate from the right ventricle, instead of originating from the left and the right ventricles, respectively. To study how Gata4 mutation causes DORV, we used a Gata4 mutant mouse model, which displays DORV. We showed that Gata4 is required in the cardiac precursor cells for the normal alignment of the great arteries. Although Gata4 mutation inhibits the rapid increase in number of the cardiac precursor cells, rescuing this defects does not recover the normal alignment of the great arteries. In addition, there is a movement problem of the cardiac precursor cells when migrating toward the great arteries during development. We further showed that a specific molecular signaling, Hh-signaling, is responsible to the Gata4 action in the cardiac precursor cells. Importantly, over-activating the Hh-signaling rescues the DORV in the Gata4 mutant embryos. This study provides an explanation for the ontogeny of CHD.

scholarly journals Individualized Surgical Reconstruction of the Right Ventricle Outflow Tract in Double Outlet Right Ventricle With Mirror Image-Dextrocardia

2021 ◽  
Vol 9 ◽  
Author(s):  
Wangping Chen ◽  
Chukwuemeka Daniel Iroegbu ◽  
Xia Xie ◽  
Wenwu Zhou ◽  
Ming Wu ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Right Ventricular ◽  
Pulmonary Stenosis ◽  
Right Ventricular Outflow Tract ◽  
Ventricular Outflow Tract ◽  
Double Outlet Right Ventricle ◽  
Mirror Image ◽  
Outflow Tract ◽  
Surgical Reconstruction ◽  
The Right

Introduction: The purpose of this study was to report our experience in the surgical reconstruction of the right ventricular outflow tract in double outlet right ventricle with a major coronary artery crossing the right ventricular outflow tract in the presence of mirror image-dextrocardia.Methods: From January 2005 to December 2019, 19 double outlet right ventricle patients (median age 4 years) with mirror image-dextrocardia and a major coronary artery crossing the right ventricular outflow tract received surgical repair. An autologous pericardial patch was used to enlarge the right ventricular outflow tract in four patients without pulmonary stenosis and three patients with mild pulmonary stenosis. A valved bovine jugular venous conduit was added to a hypoplastic native pathway in nine patients, among which six patients with moderate pulmonary stenosis received small-sized bovine jugular venous conduit implantation (diameter ≤ 16 mm). In comparison, a large-sized bovine jugular venous conduit (diameter >16 mm) was adopted in a total of three patients with severe pulmonary stenosis. Finally, three patients with preoperative pulmonary hypertension (mean pulmonary artery pressure ≥40 mmHg) did not undergo further intervention of right ventricular outflow tract due to the adequate outflow tract blood flow.Results: There was no hospital mortality. One patient with sub-pulmonary ventricular septal defect and concomitant severe pulmonary hypertension died from respiratory failure 11 months after the operation. Kaplan-Meier survival was 94% at 5, 10 years. Within a mean echocardiographic follow-up of 6.9 ± 3.6 years, a total of two patients received reintervention due to valvular stenosis of the bovine jugular venous conduit (pressure gradient > 50 mmHg at 4 and 9 years) after surgical operation. Actuarial freedom from reoperation was 90 and 72% at 5 and 10 years, respectively. During the last echocardiographic follow-up phase, all the survivors were in NYHA class I.Conclusions: Double outlet right ventricle with mirror image-dextrocardia is a rare and complicated congenital cardiac malformation. Surgical reconstruction of the right ventricular outflow tract should be individualized based on the degree of pulmonary stenosis and the specific anatomical features of each patient. Reconstructing the pulmonary artery using the various sizes of valved bovine jugular venous conduit is a safe and effective surgical method.

scholarly journals Delta-like ligand 4-mediated Notch signaling controls proliferation of second heart field progenitor cells by regulating Fgf8 expression

Development ◽  
2020 ◽  
Vol 147 (17) ◽  
pp. dev185249
Author(s):  
Prashan De Zoysa ◽  
Jiang Liu ◽  
Omar Toubat ◽  
Jongkyu Choi ◽  
Anne Moon ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Notch Signaling ◽  
Cell Biology ◽  
Ex Vivo ◽  
Notch Pathway ◽  
Double Outlet Right Ventricle ◽  
Severe Form ◽  
Second Heart Field ◽  
Early Embryonic Lethality ◽  
Heart Field

ABSTRACTThe role played by the Notch pathway in cardiac progenitor cell biology remains to be elucidated. Delta-like ligand 4 (Dll4), the arterial-specific Notch ligand, is expressed by second heart field (SHF) progenitors at time-points that are crucial in SHF biology. Dll4-mediated Notch signaling is required for maintaining an adequate pool of SHF progenitors, such that Dll4 knockout results in a reduction in proliferation and an increase in apoptosis. A reduced SHF progenitor pool leads to an underdeveloped right ventricle (RV) and outflow tract (OFT). In its most severe form, there is severe RV hypoplasia and poorly developed OFT resulting in early embryonic lethality. In its milder form, the OFT is foreshortened and misaligned, resulting in a double outlet right ventricle. Dll4-mediated Notch signaling maintains Fgf8 expression by transcriptional regulation at the promoter level. Combined heterozygous knockout of Dll4 and Fgf8 demonstrates genetic synergy in OFT alignment. Exogenous supplemental Fgf8 rescues proliferation in Dll4 mutants in ex-vivo culture. Our results establish a novel role for Dll4-mediated Notch signaling in SHF biology. More broadly, our model provides a platform for understanding oligogenic inheritance that results in clinically relevant OFT malformations.

scholarly journals The right ventricle, outflow tract, and ventricular septum comprise a restricted expression domain within the secondary/anterior heart field

2005 ◽  
Vol 287 (1) ◽  
pp. 134-145 ◽  
Author(s):  
Michael P. Verzi ◽  
David J. McCulley ◽  
Sarah De Val ◽  
Evdokia Dodou ◽  
Brian L. Black
Keyword(s):  
Right Ventricle ◽  
Outflow Tract ◽  
Ventricular Septum ◽  
Expression Domain ◽  
Heart Field ◽  
The Right ◽  
Anterior Heart Field

Incorporation of myocardial progenitors at the arterial pole of the heart

2018 ◽  
Author(s):  
Mayyasa Rammah ◽  
Francesca Rochais ◽  
Robert G. Kelly
Keyword(s):  
Heart Defects ◽  
Outflow Tract ◽  
Signalling Pathways ◽  
Second Heart Field ◽  
Proliferation And Differentiation ◽  
Life Threatening ◽  
Heart Field ◽  
Cell Niche ◽  
The Right ◽  
Epithelial Progenitor Cells

The arterial pole of the heart is a hotspot for life-threatening forms of congenital heart defects (CHDs). It is formed by progressive addition of myocardium from epithelial progenitor cells in the second heart field (SHF). SHF cells contribute successively to the right ventricle and proximal and distal outflow tract myocardial walls which, after neural crest influx and cardiac septation, give rise to myocardium at the base of the aorta and pulmonary trunk. SHF cells are characterized by continued proliferation and differentiation delay controlled by an array of transcriptional regulators and signalling pathways which define the SHF progenitor cell niche in pharyngeal mesoderm. Failure of normal SHF deployment leads to a shortened outflow tract and failure of ventriculo-arterial alignment, resulting in a spectrum of conotruncal CHD. We discuss the origins of the SHF in cardiopharyngeal mesoderm and focus on the mechanisms driving SHF deployment, summarizing current understanding of critical signalling pathways and transcription factors.

scholarly journals Gata4 potentiates second heart field proliferation and Hedgehog signaling for cardiac septation

2017 ◽  
Vol 114 (8) ◽  
pp. E1422-E1431 ◽  
Author(s):  
Lun Zhou ◽  
Jielin Liu ◽  
Menglan Xiang ◽  
Patrick Olson ◽  
Alexander Guzzetta ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Hedgehog Signaling ◽  
Cell Cycle Progression ◽  
Regulatory Element ◽  
Second Heart Field ◽  
Heart Field ◽  
Hh Signaling

GATA4, an essential cardiogenic transcription factor, provides a model for dominant transcription factor mutations in human disease. Dominant GATA4 mutations cause congenital heart disease (CHD), specifically atrial and atrioventricular septal defects (ASDs and AVSDs). We found that second heart field (SHF)-specificGata4heterozygote embryos recapitulated the AVSDs observed in germlineGata4heterozygote embryos. A proliferation defect of SHF atrial septum progenitors and hypoplasia of the dorsal mesenchymal protrusion, rather than anlage of the atrioventricular septum, were observed in this model. Knockdown of the cell-cycle repressor phosphatase and tensin homolog (Pten) restored cell-cycle progression and rescued the AVSDs.Gata4mutants also demonstrated Hedgehog (Hh) signaling defects. Gata4 acts directly upstream ofHhcomponents: Gata4 activated acis-regulatory element atGli1in vitro and occupied the element in vivo. Remarkably, SHF-specific constitutive Hh signaling activation rescued AVSDs in Gata4 SHF-specific heterozygous knockout embryos. Pten expression was unchanged inSmoothenedmutants, and Hh pathway genes were unchanged inPtenmutants, suggesting pathway independence. Thus, both the cell-cycle and Hh-signaling defects caused by dominantGata4mutations were required for CHD pathogenesis, suggesting a combinatorial model of disease causation by transcription factor haploinsufficiency.

scholarly journals GATA4 Is a Direct Transcriptional Activator of Cyclin D2 and Cdk4 and Is Required for Cardiomyocyte Proliferation in Anterior Heart Field-Derived Myocardium

2008 ◽  
Vol 28 (17) ◽  
pp. 5420-5431 ◽  
Author(s):  
Anabel Rojas ◽  
Sek Won Kong ◽  
Pooja Agarwal ◽  
Brian Gilliss ◽  
William T. Pu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Transcription Factor ◽  
Right Ventricle ◽  
Interventricular Septum ◽  
Cardiomyocyte Proliferation ◽  
Cyclin D2 ◽  
Cell Cycle Genes ◽  
Numerous Cell ◽  
Heart Field ◽  
The Right

ABSTRACT The anterior heart field (AHF) comprises a population of mesodermal progenitor cells that are added to the nascent linear heart to give rise to the majority of the right ventricle, interventricular septum, and outflow tract in mammals and birds. The zinc finger transcription factor GATA4 functions as an integral member of the cardiac transcription factor network in the derivatives of the AHF. In addition to its role in cardiac differentiation, GATA4 is also required for cardiomyocyte replication, although the transcriptional targets of GATA4 required for proliferation have not been previously identified. In the present study, we disrupted Gata4 function exclusively in the AHF and its derivatives. Gata4 AHF knockout mice die by embryonic day 13.5 and exhibit hypoplasia of the right ventricular myocardium and interventricular septum and display profound ventricular septal defects. Loss of Gata4 function in the AHF results in decreased myocyte proliferation in the right ventricle, and we identified numerous cell cycle genes that are dependent on Gata4 by microarray analysis. We show that GATA4 is required for cyclin D2, cyclin A2, and Cdk4 expression in the right ventricle and that the Cyclin D2 and Cdk4 promoters are bound and activated by GATA4 via multiple consensus GATA binding sites in each gene's proximal promoter. These findings establish Cyclin D2 and Cdk4 as direct transcriptional targets of GATA4 and support a model in which GATA4 controls cardiomyocyte proliferation by coordinately regulating numerous cell cycle genes.

scholarly journals Double-Outlet Right Ventricle in a Chianina Calf

Animals ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 318
Author(s):  
Domenico Caivano ◽  
Maria Chiara Marchesi ◽  
Piero Boni ◽  
Noemi Venanzi ◽  
Giovanni Angeli ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Septal Defect ◽  
Heart Defects ◽  
Double Outlet Right Ventricle ◽  
Cardiac Malformation ◽  
Septal Defects ◽  
Congenital Cardiac Malformation ◽  
The Right ◽  
Similar Complex ◽  
Echocardiographic Findings

Congenital heart defects have been occasionally reported in cattle and ventricular septal defect represents the most frequently encountered anomaly. The double-outlet right ventricle is a rare congenital ventriculoarterial malformation reported only in certain cattle breeds. We describe this rare and complex congenital cardiac malformation observed in a 10-day-old male Chianina calf. Clinical examination showed tachycardia, tachypnea, jugular pulses, cyanotic mucous membranes and a right apical systolic murmur. Transthoracic echocardiography revealed severe dilation of the right-sided cardiac chambers with a markedly hypoplastic left ventricle. Both aorta and pulmonary artery leaving the right ventricle in parallel alignment with the tricuspid valve were suggestive of a dual-outlet right ventricle. Interventricular and interatrial septal defects were also visualized. Post-mortem examination confirmed the echocardiographic findings. To the authors’ knowledge, a similar complex congenital cardiac malformation has not been reported in calves of the Chianina breed to date.

scholarly journals Dynamic anatomical study of cardiac shunting in crocodiles using high-resolution angioscopy

1996 ◽  
Vol 199 (2) ◽  
pp. 359-365 ◽  
Author(s):  
M Axelsson ◽  
C E Franklin ◽  
C O Löfman ◽  
S Nilsson ◽  
G C Grigg
Keyword(s):  
High Resolution ◽  
Connective Tissue ◽  
Right Ventricle ◽  
Anatomical Study ◽  
Systemic Circulation ◽  
Outflow Tract ◽  
Aortic Valves ◽  
Aortic Blood Pressure ◽  
The Right

Prolonged submergence imposes special demands on the cardiovascular system. Unlike the situation in diving birds and mammals, crocodilians have the ability to shunt blood away from the lungs, despite having an anatomically divided ventricle. This remarkable cardiovascular flexibility is due in part to three anatomical peculiarities: (1) an 'extra' aorta (the left aorta) that leaves the right ventricle and allows the blood from the right ventricle to take an alternative route into the systemic circulation instead of going to the lungs; (2) the foramen of Panizza, an aperture that connects the right and left aortas at their base immediately outside the ventricle; and (3) a set of connective tissue outpushings in the pulmonary outflow tract in the right ventricle. Using high-resolution angioscopy, we have studied these structures in the beating crocodile heart and correlated their movements with in vivo pressure and flow recordings. The connective tissue outpushings in the pulmonary outflow tract represent an active mechanism used to restrict blood flow into the lungs, thus creating one of the conditions required for a right-to-left shunt. We observed that the foramen of Panizza was obstructed by the medial cusp of the right aortic valve during most of systole, effectively differentiating the left and right aortic blood pressure. During diastole, however, the foramen remained open, allowing pressure equilibration between the two aortas. Contrary to current theories, we found that the left aortic valves were unable to cover the foramen of Panizza during any part of the cardiac cycle, supporting the reversed foramen flow hypothesis. This would ensure a supply of blood to the coronary and cephalic circulation during a complete shut-down of the left side of the heart, such as might occur during prolonged submergence.

scholarly journals Results of Hemodynamic Correction in Patients with Double Outlet Right Ventricle

2019 ◽  
pp. 55-60
Author(s):  
Kh. K. Abralov ◽  
O. Kh. Karimov ◽  
S. O. Siromakha ◽  
I. V. Dziuriy ◽  
Ya. P. Truba ◽  
...  
Keyword(s):  
Right Ventricle ◽  
Tricuspid Valve ◽  
Double Outlet Right Ventricle ◽  
Outflow Tract ◽  
Hemodynamic Parameters ◽  
Mixed Form ◽  
Cavopulmonary Anastomosis ◽  
Common Ventricle ◽  
The Common

Aim. To analyze results of hemodynamic correction in surgical treatment of double outlet right ventricle (DORV). Маterials and methods. For the period from January 1996 to September 2017, 31 (6.03 % of total number of patients with DORV) patients underwent hemodynamic correction of DORV. The age of the patients ranged from 1 to 19 years (71.2 ± 50.5 months on the average). The weight of the patients ranged from 9 to 41 kg (19.6 ± 11.3 kg on the average). Of these, 19 (61.3 %) were male patients and 12 (38.7 %) were female patients. The overwhelming majority (25 (80.6 %)) of the patients were diagnosed with transposition-type DORV. The anatomy of DORV with non-committed ventricular septal defect was observed in 5 (16.1 %) patients. In one patient (3.1 %), the anatomy of DORV (in the form of tetralogy of Fallot) was combined with tricuspid valve atresia. Results. The main reasons of hemodynamic correction in 16 (51.6 %) cases was LV hypoplasia. In 2 cases it was combined with tricuspid valve (TV) straddling, and in 2 cases it was an integral part of the unbalanced form of complete atrio-ventricular communication (AVC). In one case (3.1 %), the unbalanced form of complete AVC was combined with a mixed form of the common ventricle. The mixed form of the common ventricle was the reason of hemodynamic correction in 9 (29 %) patients. In 2 (6.2 %) cases, hemodynamic correction was performed due to the anatomy of the RV hypoplasia. In the remaining 2 patients, anatomy of the common ventricle was not diagnosed, but a combination of other concomitant defects was a contraindication to biventricular correction. Palliative operations (Blalock-Taussig shunt, BTS) as the first stage of correction were performed in 16 (51.6 %) patients. In 2 patients with LV outflow tract obstruction, systemic-pulmonary anastomosis was applied in combination with plastic repair of the great vessel roots using the proprietary technique for elimination of the left ventricular outflow tract (LVOT) stenosis. Bidirectional cavopulmonary anastomosis (BCPA) was applied in 29 (93.5 %) cases. Of these, 4 (13.8 %) patients subsequently underwent total cavopulmonary anastomosis (TCPA) procedure. Two patients with good hemodynamic parameters underwent TCPA without prior palliative procedures. Conclusion. Palliative surgery as the first stage to hemodynamic correction is accompanied by significant improvement in hemodynamic parameters of patients. Application of BCPA as the second stage of hemodynamic correction provides good results and is required to prepare the patient for TCPA. The long-term period is characterized by improvement in the quality of life in patients with complex DORV. In the long-term period, 85.2 % of patients are classified as NYHA FC I.

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