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The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling.

ABSTRACT: Cardiac septum malformations account for the largest proportion in congenital heart defects. The transcription factor Sox7 has critical functions in the vascular development and angiogenesis. It is unclear whether Sox7 also contributes to cardiac septation development. We identified a de novo 8p23.1 deletion with Sox7 haploinsufficiency in an atrioventricular septal defect (AVSD) patient using whole exome sequencing in 100 AVSD patients. Then, multiple Sox7 conditional loss-of-function mice models were generated to explore the role of Sox7 in atrioventricular cushion development. Sox7 deficiency mice embryos exhibited partial AVSD and impaired endothelial to mesenchymal transition (EndMT). Transcriptome analysis revealed BMP signaling pathway was significantly downregulated in Sox7 deficiency atrioventricular cushions. Mechanistically, Sox7 deficiency reduced the expressions of Bmp2 in atrioventricular canal myocardium and Wnt4 in endocardium, and Sox7 binds to Wnt4 and Bmp2 directly. Furthermore, WNT4 or BMP2 protein could partially rescue the impaired EndMT process caused by Sox7 deficiency, and inhibition of BMP2 by Noggin could attenuate the effect of WNT4 protein. In summary, our findings identify Sox7 as a novel AVSD pathogenic candidate gene, and it can regulate the EndMT involved in atrioventricular cushion morphogenesis through Wnt4-Bmp2 signaling. This study contributes new strategies to the diagnosis and treatment of congenital heart defects.

SUBMITTER: Hong N

PROVIDER: S-EPMC8041771 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Due to advances in corrective surgery, congenital heart disease has an ever growing patient population. Atrial arrhythmias are frequently observed pre- and post-surgical correction. Pharmaceutical antiarrhythmic therapy is not always effective, therefore many symptomatic patients undergo catheter ablation therapy. In patients with atrioventricular septal defects (AVSD), ablation therapy itself has mixed success; arrhythmogenic recurrences are common, and because of the anatomical displacement of the atrioventricular node, 3-degree heart block post-ablation is a real concern. In order to develop optimal and safe ablation strategies, the field of congenital cardiac electrophysiology must combine knowledge from clinical electrophysiology with a thorough understanding of the anatomical substrates for arrhythmias. Using image-based analysis and multi-cellular mathematical modeling of electrical activation, we show how the anatomical alterations characteristic of an AVSD serve as arrhythmogenic substrates. Using ex-vivo contrast enhanced micro-computed tomography we imaged post-mortem the heart of a 5 month old male with AVSD at an isometric spatial resolution of 38 ?m. Morphological analysis revealed the 3D disposition of the cardiac conduction system for the first time in an intact heart with this human congenital malformation. We observed displacement of the compact atrioventricular node inferiorly to the ostium of the coronary sinus. Myocyte orientation analysis revealed that the normal arrangement of the major atrial muscle bundles was preserved but was modified in the septal region. Models of electrical activation suggest the disposition of the myocytes within the atrial muscle bundles associated with the "fast pathway," together with the displaced atrioventricular node, serve as potential substrates for re-entry and possibly atrial fibrillation. This study used archived human hearts, showing them to be a valuable resource for the mathematical modeling community, and opening new possibilities for the investigations of arrhythmogenesis and ablation strategies in the congenitally malformed heart.

Project description:BackgroundUniatrial biventricular connection (UBC) is a rare cardiovascular anomaly characterized by absence of one atrioventricular connection and drainage of the other atrium via a solitary atrioventricular valve into both ventricles. The absent atrioventricular connection may affect either the left or right atrium. Because of the absence of one atrioventricular connection hearts with UBC have been classified among functionally univentricular hearts requiring palliative treatment according to the Fontan principle.Aims/objectiveWe report two further patients with UBC. In one of these patients careful echocardiographic examination of the atrioventricular junction in early infancy revealed the possibility of biventricular repair based on the favorable anatomy of the atrioventricular valve and balanced ventricles in the presence of an inlet ventricular septal defect (VSD).Case presentationsBoth patients presented in the neonatal period for evaluation of complex congenital heart disease. The anatomy of the atrioventricular valves in our patients was indistinguishable from atrioventricular septal defects exhibiting the morphology of a common valve with superior and inferior bridging leaflets. The common atrioventricular valve was connected exclusively to the right atrium draining into both ventricles while the left atrium drained into the right atrium via a secundum atrial septal defect. In one of our patients biventricular repair with good longterm-result was performed by reseptation of the atria, patch repair of the VSD and septation of the atrioventricular valve. The second patient underwent univentricular palliation according to the Fontan principle.Discussion/conclusionThe echocardiographic findings in our patients suggest that at least some patients with UBC represent a variant of atrioventricular septal defects associated with extreme ventriculoatrial malalignment resulting in fusion of the deviated primary atrial septum with the lateral aspect of the atrioventricular junction. This offers the option of septation of the common atrioventricular valve and biventricular repair in patients with adequate size of both ventricles. Exact echocardiographic analysis of the morphology of the atrioventricular valve is essential to distinguish these patients with a morphologically common atrioventricular valve in early infancy from other variants of absent atrioventricular connection and to select those who are suitable for biventricular repair.

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The transcription factor Sox7 modulates endocardiac cushion formation contributed to atrioventricular septal defect through Wnt4/Bmp2 signaling.

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