Published online before print April 5, 2007, doi: 10.1161/01.RES.0000266605.63681.5a
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Submitted on September 12, 2006
Revised on March 23, 2007
Accepted on March 27, 2007
-Catenin Downregulation Is Required for Adaptive Cardiac Remodeling
Anthony Baurand ;
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.
* To whom correspondence should be addressed. E-mail: martin.bergmann{at}charite.de.
The armadillo-related protein 
-catenin has multiple functions in cardiac tissue homeostasis: stabilization of -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 -catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible 
MHC-CrePR1 transgene was used to induce -catenin depletion (loxP-flanked exons 3 to 6, -cat
ex3-6 mice) or stabilization (loxP-flanked exon 3, -catex3 mice). Levels of -catenin were altered both in membrane and nuclear extracts. Analysis of the -catenin target genes Axin2 and Tcf-4 confirmed increased -catenin-dependent transcription in -catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. -Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with -catenin depletion. In contrast, mice with stabilized -catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing -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 -catenin-stabilized mice. These data suggest that -catenin downregulation is required for adaptive cardiac hypertrophy.
Key words: transcription factor • signaling •
-catenin •
hypertrophy •
development
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