title: Activation of endothelial β-catenin signaling induces heart failure.
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.
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Akito
authors.initials: A
authors.lastname: Nakagawa
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.|Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|Japan Agency for Medical Research and Development, AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.|Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Atsuhiko T
authors.initials: AT
authors.lastname: Naito
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|Japan Agency for Medical Research and Development, AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Sumida
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Seitaro
authors.initials: S
authors.lastname: Nomura
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Shibamoto
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Tomoaki
authors.initials: T
authors.lastname: Higo
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Katsuki
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Taku
authors.initials: T
authors.lastname: Sakai
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Hashimoto
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kuramoto
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Oka
authors.affiliation: Japan Agency for Medical Research and Development, AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.|Department of Cardiovascular Regenerative Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Jong-Kook
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Harada
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazutaka
authors.initials: K
authors.lastname: Ueda
authors.affiliation: Department of Medicine II, Kansai Medical University, Hirakata, Osaka 573-1191, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Shiojima
authors.affiliation: Experimentelle Gefäßmedizin und Transplantationsforschung/ Koordinator Hypertoniezentrum, Klinik für Nieren- und Hochdruckerkrankungen, Medizinische Hochschule Hannover Carl-Neubergstr. 130625 Hannover, Germany.
authors.forename: Florian P
authors.initials: FP
authors.lastname: Limbourg
authors.affiliation: Max Planck Institute for Molecular Biomedicine, Department of Tissue Morphogenesis, University of Münster, Faculty of Medicine, Münster, Germany.
authors.forename: Ralf H
authors.initials: RH
authors.lastname: Adams
authors.affiliation: Department of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, Koto-ku, Tokyo 135-8550, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.affiliation: Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Sakata
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|Japan Agency for Medical Research and Development, AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Akazawa
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.|Japan Agency for Medical Research and Development, AMED-CREST, Chiyoda-ku, Tokyo 100-0004, Japan.
authors.forename: Issei
authors.initials: I
authors.lastname: Komuro
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000502:physiology*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006333:Heart Failure / Q000503:physiopathology*; D051379:Mice; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors*; D016019:Survival Analysis; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C495267:CTNNB1 protein, mouse; D020890:Neuregulin-1; C490581:Nrg1 protein, mouse; D051176:beta Catenin; D066246:ErbB Receptors