Endocardial Fibroelastosis Is Caused by Aberrant Endothelial to Mesenchymal Transition

2015 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Endocardial Fibroelastosis Is Caused by Aberrant Endothelial to Mesenchymal Transition​
Xu, X.; Friehs, I.; Hu, T. Z.; Melnychenko, I.; Tampe, B. ; Alnour, F.   & Iascone, M. et al.​ (2015) 
Circulation Research116(5) pp. 857​-866​.​ DOI: https://doi.org/10.1161/CIRCRESAHA.116.305629 

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Authors
Xu, Xingbo; Friehs, Ingeborg; Hu, Tachi Zhong; Melnychenko, Ivan; Tampe, Björn ; Alnour, Fouzi ; Iascone, Maria; Kalluri, Raghu; Zeisberg, Michael ; del Nido, Pedro J.; Zeisberg, Elisabeth M. 
Abstract
Rationale: Endocardial fibroelastosis (EFE) is a unique form of fibrosis, which forms a de novo subendocardial tissue layer encapsulating the myocardium and stunting its growth, and which is typically associated with congenital heart diseases of heterogeneous origin, such as hypoplastic left heart syndrome. Relevance of EFE was only recently highlighted through the establishment of staged biventricular repair surgery in infant patients with hypoplastic left heart syndrome, where surgical removal of EFE tissue has resulted in improvement in the restrictive physiology leading to the growth of the left ventricle in parallel with somatic growth. However, pathomechanisms underlying EFE formation are still scarce, and specific therapeutic targets are not yet known. Objective: Here, we aimed to investigate the cellular origins of EFE tissue and to gain insights into the underlying molecular mechanisms to ultimately develop novel therapeutic strategies. Methods and Results: By utilizing a novel EFE model of heterotopic transplantation of hearts from newborn reporter mice and by analyzing human EFE tissue, we demonstrate for the first time that fibrogenic cells within EFE tissue originate from endocardial endothelial cells via aberrant endothelial to mesenchymal transition. We further demonstrate that such aberrant endothelial to mesenchymal transition involving endocardial endothelial cells is caused by dysregulated transforming growth factor beta/bone morphogenetic proteins signaling and that this imbalance is at least in part caused by aberrant promoter methylation and subsequent transcriptional suppression of bone morphogenetic proteins 5 and 7. Finally, we provide evidence that supplementation of exogenous recombinant bone morphogenetic proteins 7 effectively ameliorates endothelial to mesenchymal transition and experimental EFE in rats. Conclusions: In summary, our data point to aberrant endothelial to mesenchymal transition as a common denominator of infant EFE development in heterogeneous, congenital heart diseases, and to bone morphogenetic proteins 7 as an effective treatment for EFE and its restriction of heart growth.
Issue Date
2015
Journal
Circulation Research 
Project
SFB 1002: Modulatorische Einheiten bei Herzinsuffizienz 
SFB 1002 | C01: Epigenetische Kontrolle der Herzfibrose 
Working Group
RG E. Zeisberg (Kardiales Stroma) 
RG M. Zeisberg (Renale Fibrogenese) 
External URL
https://sfb1002.med.uni-goettingen.de/production/literature/publications/114
ISSN
1524-4571; 0009-7330
Language
English

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