Activation of endothelial ß-catenin signaling induces heart failure.
Sci Rep
; 6: 25009, 2016 05 05.
Article
em En
| MEDLINE
| ID: mdl-27146149
ABSTRACT
Activation of ß-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/ß-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of ß-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of ß-catenin, which activates Wnt/ß-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/ß-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/ß-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neuregulina-1
/
Células Endoteliais
/
Beta Catenina
/
Via de Sinalização Wnt
/
Receptores ErbB
/
Insuficiência Cardíaca
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Japão