β-Catenin downregulation is required for adaptive cardiac remodeling

被引:127
作者
Baurand, Anthony
Zelarayan, Laura
Betney, Russell
Gehrke, Christina
Dunger, Sandra
Noack, Claudia
Busjahn, Andreas
Huelsken, Joerg
Taketo, Makoto Mark
Birchmeier, Walter
Dietz, Rainer
Bergmann, Martin W.
机构
[1] Franz Volhard Clin, D-13125 Berlin, Germany
[2] HELIOS Klinikum Berlin, Franz Volhard Klin, Charite Universitatsmed, Buch, Germany
[3] Max Delbruck Ctr Mol Med, Berlin, Germany
[4] HealthTwiSt GmbH, Berlin, Germany
[5] Inst Suisse Rech Expt Canc, Epalinges, Switzerland
[6] Kyoto Univ, Grad Sch Med, Dept Pharmacol, Kyoto, Japan
关键词
transcription factor; signaling; beta-catenin; hypertrophy; development;
D O I
10.1161/01.RES.0000266605.63681.5a
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 alpha MHC-CrePR1 transgene was used to induce beta-catenin depletion (loxP-flanked exons 3 to 6, beta-cat(Delta ex3-6) mice) or stabilization (loxP-flanked exon 3, beta-cat(Delta ex3) 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.
引用
收藏
页码:1353 / 1362
页数:10
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