Wnt5a-YAP signaling axis mediates mechanotransduction in cardiac myocytes and contributes to contractile dysfunction induced by pressure overload.

Non-canonical Wnt signaling activated by Wnt5a/Wnt11 is required for the second heart field development in mice. However, the pathophysiological role of non-canonical Wnt signaling in the adult heart has not been fully elucidated. Here we show that cardiomyocyte-specific knockout mice exhibit improved systolic function and reduced expression of mechanosensitive genes including when subjected to pressure overload. In cultured cardiomyocytes, knockdown reduced upregulation induced by cyclic cell stretch. Upstream analysis revealed that TEAD1, a transcription factor that acts with Hippo pathway co-activator YAP, was downregulated both and by knockdown/knockout. YAP nuclear translocation was induced by cell stretch and attenuated by knockdown. knockdown-induced downregulation during cell stretch was rescued by Hippo inhibition, and the rescue effect was canceled by knockdown of . These results collectively suggest that Wnt5a-YAP signaling axis mediates mechanotransduction in cardiomyocytes and contributes to heart failure progression.