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Beta-catenin downregulation is required for adaptive cardiac remodeling

Item Type:Article
Title:Beta-catenin downregulation is required for adaptive cardiac remodeling
Creators Name:Baurand, A. and Zelarayan, L. and Betney, R. and Gehrke, C. and Dunger, S. and Noack, C. and Busjahn, A. and Huelsken, J. and Taketo, M.M. and Birchmeier, W. and Dietz, R. and Bergmann, M.W.
Abstract:The armadillo-related protein beta-catenin has multiple functions in cardiac tissue homeostasis: stabilization of beta-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 beta-catenin in adult cardiac hypertrophy initiated by angiotensin II (Ang II). The cardiac-specific mifepristone-inducible alphaMHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Deltaex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Deltaex3) mice). Levels of beta-catenin were altered both in membrane and nuclear extracts. Analysis of the beta-catenin target genes Axin2 and Tcf-4 confirmed increased beta-catenin-dependent transcription in beta-catenin stabilized mice. In both models, transgenic mice were viable and healthy at age 6 months. beta-Catenin appeared dispensable for cell membrane function. Ang II infusion induced cardiac hypertrophy both in wild-type mice and in mice with beta-catenin depletion. In contrast, mice with stabilized beta-catenin had decreased cross-sectional area at baseline and an abrogated hypertrophic response to Ang II infusion. Stabilizing beta-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 beta-catenin-stabilized mice. These data suggest that beta-catenin downregulation is required for adaptive cardiac hypertrophy.
Keywords:Transcription factor, Signaling, Beta-catenin, Hypertrophy, Development, Animals, Mice
Source:Circulation Research
Publisher:American Heart Association
Page Range:1353-1362
Date:11 May 2007
Official Publication:https://doi.org/10.1161/01.RES.0000266605.63681.5a
PubMed:View item in PubMed

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