Beta-catenin downregulation is required for adaptive cardiac remodeling.
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.
Baurand
Anthony
A
Max Delbrück Center for Molecular Medicine, Berlin, Germany.
Zelarayan
Laura
L
Betney
Russell
R
Gehrke
Christina
C
Dunger
Sandra
S
Noack
Claudia
C
Busjahn
Andreas
A
Huelsken
Joerg
J
Taketo
Makoto Mark
MM
Birchmeier
Walter
W
Dietz
Rainer
R
Bergmann
Martin W
MW
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D005786:Gene Expression Regulation; D018975:Insulin-Like Growth Factor Binding Protein 5 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D020825:T-Box Domain Proteins / Q000235:genetics; D020257:Ventricular Remodeling; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
D018975:Insulin-Like Growth Factor Binding Protein 5; D020825:T-Box Domain Proteins; C486013:Tbx20 protein, mouse; D051176:beta Catenin; D000804:Angiotensin II