Endocardial HDAC3 is required for myocardial trabeculation

Jihyun Jang, Mette Bentsen, Ye Jun Kim, Erick Kim, Vidu Garg, Chen-Leng Cai, Mario Looso and Deqiang Li ()
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Jihyun Jang: Nationwide Children’s Hospital
Mette Bentsen: Max Planck Institute for Heart and Lung Research
Ye Jun Kim: University of Maryland School of Medicine
Erick Kim: University of Maryland School of Medicine
Vidu Garg: Nationwide Children’s Hospital
Chen-Leng Cai: Indiana University School of Medicine
Mario Looso: Max Planck Institute for Heart and Lung Research
Deqiang Li: Nationwide Children’s Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract Failure of proper ventricular trabeculation is often associated with congenital heart disease. Support from endocardial cells, including the secretion of extracellular matrix and growth factors is critical for trabeculation. However, it is poorly understood how the secretion of extracellular matrix and growth factors is initiated and regulated by endocardial cells. We find that genetic knockout of histone deacetylase 3 in the endocardium in mice results in early embryo lethality and ventricular hypotrabeculation. Single cell RNA sequencing identifies significant downregulation of extracellular matrix components in histone deacetylase 3 knockout endocardial cells. Secretome from cultured histone deacetylase 3 knockout mouse cardiac endothelial cells lacks transforming growth factor ß3 and shows significantly reduced capacity in stimulating cultured cardiomyocyte proliferation, which is remarkably rescued by transforming growth factor ß3 supplementation. Mechanistically, we identify that histone deacetylase 3 knockout induces transforming growth factor ß3 expression through repressing microRNA-129-5p. Our findings provide insights into the pathogenesis of congenital heart disease and conceptual strategies to promote myocardial regeneration.

Date: 2024
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DOI: 10.1038/s41467-024-48362-6

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