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          Institute: MPI für molekulare Biomedizin     Collection: Jahrbuch 2017 (publ. 2016, arch)     Display Documents



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ID: 732120.0, MPI für molekulare Biomedizin / Jahrbuch 2017 (publ. 2016, arch)
Activation of endothelial beta-catenin signaling induces heart failure
Authors:Nakagawa, A.; Naito, A. T.; Sumida, T.; Nomura, S.; Shibamoto, M.; Higo, T.; Okada, K.; Sakai, T.; Hashimoto, A.; Kuramoto, Y.; Oka, T.; Lee, J. K.; Harada, M.; Ueda, K.; Shiojima, I.; Limbourg, F. P.; Adams, R. H.; Noda, T.; Sakata, Y.; Akazawa, H.; Komuro, I.
Date of Publication (YYYY-MM-DD):2016-05
Title of Journal:Scientific Reports
Volume:6
Start Page:9
Review Status:Internal review
Audience:Not Specified
Abstract / Description: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.
Free Keywords:neuregulin receptor erbb2; dilated cardiomyopathy; cardiac-hypertrophy; stem-cells; disease; pathway; angiogenesis; mutations; models; muscle; Science & Technology - Other Topics
External Publication Status:published
Document Type:Article
Communicated by:Jeanine Müller-Keuker
Affiliations:MPI für molekulare Biomedizin
External Affiliations:Naito, AT (reprint author), Osaka Univ, Grad Sch Med, Dept Cardiovasc Med, Suita, Osaka 5650871, Japan.; Naito, AT; Komuro, I (reprint author), Univ Tokyo, Grad Sch Med, Dept Cardiovasc Med, Bunkyo Ku, Tokyo 1138655, Japan.; Naito, AT; Komuro, I (reprint author), AMED CREST, Japan Agcy Med Res & Dev, Chiyoda Ku, Tokyo 1000004, Japan.; Naito, AT (reprint author), Osaka Univ, Grad Sch Med, Dept Cardiovasc Regenerat Med, Suita, Osaka 5650871, Japan. atnaito0508@gmail.com; komuro-tky@umin.ac.jp %G English
Identifiers:ISSN:2045-2322 %R 10.1038/srep25009 %] 25009 [ID No:1]
URL:<Go to ISI>://WOS:000375474400001 [ID No:2]
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