Wnt5a-YAP signaling axis mediates mechanotransduction in cardiac myocytes and contributes to the transition to heart failure (rat sample)

Non-canonical Wnt signaling activated by Wnt5a and Wnt11 is required for the development of second heart field cardiac progenitor cells 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 Wnt5a knockout mice exhibit improved systolic function and reduced expression of mechanosensitive genes including Nppb compared to control mice when subjected to pressure overload. In cultured cardiac myocytes, Wnt5a knockdown reduces the upregulation of Nppb gene expression and YAP nuclear translocation induced by cyclic cell stretch. Wnt5a knockdown-induced Nppb downregulation in response to cell stretch is rescued by inhibition of Hippo pathway, and the rescue effect of Hippo inhibition is canceled by YAP knockdown. These results collectively suggest that Wnt5a-YAP signaling axis mediates mechanotransduction in cardiac myocytes and contributes to the transition to heart failure.由Wnt5a与Wnt11激活的非经典Wnt信号通路（non-canonical Wnt signaling）对小鼠第二心区心脏祖细胞的发育至关重要。然而，非经典Wnt信号通路在成年心脏中的病理生理作用尚未完全阐明。本研究发现，与对照组小鼠相比，心肌细胞特异性敲除Wnt5a的小鼠在承受压力负荷时，其收缩功能得到改善，且包括Nppb在内的机械敏感基因的表达水平显著降低。在体外培养的心肌细胞中，敲低Wnt5a可减少周期性细胞牵张诱导的Nppb基因表达上调以及YAP（Yes-associated protein）核转位。针对细胞牵张刺激下由Wnt5a敲低所诱导的Nppb表达下调，通过抑制Hippo信号通路（Hippo pathway）可使其得到挽救，而该挽救效应会因YAP敲低而被抵消。综上，本研究结果表明，Wnt5a-YAP信号轴介导心肌细胞的机械转导过程，并参与心力衰竭的发生发展。