Activation of endothelial β-catenin signaling induces heart failure.

Akito Nakagawa,Florian P Limbourg,Seitaro Nomura,Issei Komuro,Yuki Kuramoto,Jong-Kook Lee,Tetsuo Noda,Hiroshi Akazawa,Atsuhiko T Naito,Kazutaka Ueda,Tomokazu Sumida,Tomoaki Higo,Mutsuo Harada,Ralf H Adams,Yasushi Sakata,Katsuki Okada,Masato Shibamoto,Ichiro Shiojima,Akihito Hashimoto,Tôru Oka ,Tomohiro Sakai

doi:10.1038/srep25009

Abstract

Activation of β-catenin-dependent canonical Wnt signaling in endothelial cells plays a key role in angiogenesis during development and ischemic diseases, however, other roles of Wnt/β-catenin signaling in endothelial cells remain poorly understood. Here, we report that sustained activation of β-catenin signaling in endothelial cells causes cardiac dysfunction through suppressing neuregulin-ErbB pathway in the heart. Conditional gain-of-function mutation of β-catenin, which activates Wnt/β-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/β-catenin signaling in endothelial cells might be a cause of heart failure through suppressing neuregulin-ErbB signaling, and that the Wnt/β-catenin/NRG axis in cardiac endothelial cells might become a therapeutic target for heart failure.

Highlights

Phosphorylation/ubiquitination site responsible for its proteasomal degradation
Wnt/β -catenin signaling plays an important role in cardiac hypertrophy and ischemic injury[25,26,27], little is known about the role of Wnt/β -catenin signaling in heart failure
We showed that sustained activation of β -catenin signaling in Endothelial cells (ECs) induces heart failure in adult mice

Summary

Introduction

Phosphorylation/ubiquitination site responsible for its proteasomal degradation. Knock-in mice with LoxP sequence flanking exon 3 of β -catenin gene (Ctnnb1lox(ex3)/lox(ex3) mice) generates β -catenin protein lacking its exon 3 (β -catenin (Δ ex3)) after Cre-mediated recombination and is widely used as a mice model for conditional activation of Wnt/β -catenin signaling together with cell type-specific Cre mice[12]. Previous reports used Ctnnb1lox(ex3)/lox(ex3) mice to investigate the roles of endothelial Wnt/β -catenin signaling in angiogenesis during embryonic development and ischemia. Sustained activation of Wnt/β -catenin signaling in ECs blocks vascular remodeling in early embryonic development[13] whereas activation of Wnt/β -catenin signaling in ECs promotes angiogenesis after myocardial infarction[14]. Using a transgenic mouse model with tamoxifen (TAM)-inducible, endothelial-specific expression of β -catenin (Δ ex3), we found that sustained activation of β -catenin signaling in ECs impairs cardiac function leading to severe heart failure. Administration of recombinant NRG1 ameliorated ErbB signaling and cardiac function of the transgenic mice. These results suggest that sustained activation of β -catenin signaling in ECs causes heart failure in a NRG-ErbB signaling dependent manner

Methods

Results

Conclusion