Beta-catenin downregulation is required for adaptive cardiac remodeling

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Item Type:	Article
Title:	Beta-catenin downregulation is required for adaptive cardiac remodeling
Creators Name:	Baurand, A., Zelarayan, L., Betney, R., Gehrke, C., Dunger, S., Noack, C., Busjahn, A., Huelsken, J., Taketo, M.M., Birchmeier, W., 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
ISSN:	0009-7330
Publisher:	American Heart Association
Volume:	100
Number:	9
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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