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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 beta 3 and shows significantly reduced
capacity in stimulating cultured cardiomyocyte proliferation, which is
remarkably rescued by transforming growth factor beta 3 supplementation.
Mechanistically, we identify that histone deacetylase 3 knockout induces
transforming growth factor beta 3 expression through repressing
microRNA-129-5p. Our findings provide insights into the pathogenesis of
congenital heart disease and conceptual strategies to promote myocardial
regeneration.