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bioRxiv · 10.1101/2021.07.02.450976

ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium

Bi, Y.·Yang, Z.·Jin, M.·Zhai, K.·Wang, J.·Mao, Y.·Liu, Y.·Ding, M.·Wang, H.·Wang, F.·Ji, G.
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Abstract

Rationale: Endocardial cushions are precursors of the valvoseptal complex that separates the four heart chambers and control blood flow through the heart. Abnormalities in endocardial cushion development lead to atrioventricular septal defects (AVSDs), which affect 1 in 2,100 live births. Several genes have been implicated in the development of endocardial cushions. Specifically, endoplasmic reticulum-resident protein 44 (ERp44) has been found to play a role in the early secretory pathway, but its function in heart development has not been well studied. Objective: The goal of this study was to investigate the role of ERp44 in heart development in mice. Approach and Results: Using conventional and tissue-specific knockout mouse models, we demonstrated that ERp44 plays a specific role in heart development. ERp44 knockout (KO) mice were smaller in size, and most mice died during early postnatal life. KO hearts exhibited the typical phenotypes of congenital heart diseases, such as abnormal heart shapes as well as severe septal and valvular defects. Similar phenotypes were found in cTnt-cre+/-; Erp44fl/fl mice, which indicated that myocardial ERp44 principally controls endocardial cushion formation. Further studies demonstrated that the deletion of ERp44 significantly decreased the proliferation of cushion cells and impaired the endocardial-mesenchymal transition (EndMT), which was followed by endocardial cushion dysplasia. Finally, we found that ERp44 directly bound to VEGFA and controlled its release. Conclusions: ERp44 contributes to the development of the endocardial cushion by affecting the EndMT of cushion cells by regulating VEGFA release in myocardial cells.

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Bi, Y., Yang, Z., Jin, M., Zhai, K., Wang, J., Mao, Y., Liu, Y., Ding, M., Wang, H., Wang, F., Ji, G.. 2021-07-03. ERp44 is Required for Endocardial Cushion Development by Regulating VEGFA Secretion in Myocardium. https://doi.org/10.1101/2021.07.02.450976

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