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(Circulation Research. 2007;100:1353.)
© 2007 American Heart Association, Inc.

Integrative Physiology

ß-Catenin Downregulation Is Required for Adaptive Cardiac Remodeling

Anthony Baurand^*, Laura Zelarayan^*, Russell Betney, Christina Gehrke, Sandra Dunger, Claudia Noack, Andreas Busjahn, Joerg Huelsken, Makoto Mark Taketo, Walter Birchmeier, Rainer Dietz, Martin W. Bergmann

From the Max Delbrück Center for Molecular Medicine (A. Baurand, L.Z., C.N., W.B., M.W.B.), Berlin, Germany; Department of Cardiology (R.B., C.G., S.D., R.D., M.W.B.), Campus Buch and Campus Virchow–Klinikum, Charité–Universitätsmedizin Berlin, Franz Volhard Klinik, HELIOS Klinikum Berlin–Buch, Germany; HealthTwiSt GmbH (A. Busjahn), Berlin, Germany; Institut Suisse de Recherche Expérimentale sur le Cancer (J.H.), Epalinges, Switzerland; and Department of Pharmacology (M.M.T.), Graduate School of Medicine, Kyoto University, Japan.

Correspondence to Martin W. Bergmann, MD, Franz Volhard Clinic, Wiltbergstrasse 50, 13125 Berlin, Germany. E-mail martin.bergmann{at}charite.de

The armadillo-related protein ß-catenin has multiple functions in cardiac tissue homeostasis: stabilization of ß-catenin has been implicated in adult cardiac hypertrophy, and downregulation initiates heart formation in embryogenesis. The protein is also part of the cadherin/catenin complex at the cell membrane, where depletion might result in disturbed cell–cell interaction similar to N-cadherin knockout models. Here, we analyzed the in vivo role of ß-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible MHC-CrePR1 transgene was used to induce ß-catenin depletion (loxP-flanked exons 3 to 6, ß-cat^ex3–6 mice) or stabilization (loxP-flanked exon 3, ß-cat^ex3 mice). Levels of ß-catenin were altered both in membrane and nuclear extracts. Analysis of the ß-catenin target genes Axin2 and Tcf-4 confirmed increased ß-catenin–dependent transcription in ß-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. ß-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with ß-catenin depletion. In contrast, mice with stabilized ß-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing ß-catenin led to impaired fractional shortening compared with control littermates after Ang II stimulation. This functional deterioration was associated with altered expression of the T-box proteins Tbx5 and Tbx20 at baseline and after Ang II stimulation. In addition, atrophy-related protein IGFBP5 was upregulated in ß-catenin–stabilized mice. These data suggest that ß-catenin downregulation is required for adaptive cardiac hypertrophy.

Key Words: transcription factor • signaling • ß-catenin • hypertrophy • development

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