Activation of endothelial beta-catenin signaling induces heart failure

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

来源：Scientific Reports, 2016, 6(1): 25009.

DOI：10.1038/srep25009

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

• 出版日期2016-5-5