Activation of endothelial ?-catenin signaling induces heart failure.

ABSTRACT: Activation of ?-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/?-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of ?-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of ?-catenin, which activates Wnt/?-catenin signaling in Bmx-positive arterial endothelial cells (Bmx/CA mice) led to progressive cardiac dysfunction and 100% mortality at 40 weeks after tamoxifen treatment. Electron microscopic analysis revealed dilatation of T-tubules and degeneration of mitochondria in cardiomyocytes of Bmx/CA mice, which are similar to the changes observed in mice with decreased neuregulin-ErbB signaling. Endothelial expression of Nrg1 and cardiac ErbB signaling were suppressed in Bmx/CA mice. The cardiac dysfunction of Bmx/CA mice was ameliorated by administration of recombinant neuregulin protein. These results collectively suggest that sustained activation of Wnt/?-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/?-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.

SUBMITTER: Nakagawa A 

PROVIDER: S-EPMC4857119 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature