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TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice

Nature Medicine volume 6, pages 556–563 (2000)Cite this article

Abstract

The transforming-growth-factor-β-activated kinase TAK1 is a member of the mitogen-activated protein kinase kinase kinase family, which couples extracellular stimuli to gene transcription. The in vivo function of TAK1 is not understood. Here, we investigated the potential involvement of TAK1 in cardiac hypertrophy. In adult mouse myocardium, TAK1 kinase activity was upregulated 7 days after aortic banding, a mechanical load that induces hypertrophy and expression of transforming growth factor β. An activating mutation of TAK1 expressed in myocardium of transgenic mice was sufficient to produce p38 mitogen-activated protein kinase phosphorylation in vivo , cardiac hypertrophy, interstitial fibrosis, severe myocardial dysfunction, ‘fetal’ gene induction, apoptosis and early lethality. Thus, TAK1 activity is induced as a delayed response to mechanical stress, and can suffice to elicit myocardial hypertrophy and fulminant heart failure.

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Figure 1: TAK1 expression and activity in myocardium.
Figure 2: TAK1 and p38, in series, mediate TGF-β signaling to the SkA promoter.
Figure 3: TAK1 signaling to the SkA promoter through SRF and the SRF co-activator ATF6.
Figure 4: TGF-β induces p38-dependent phosphorylation of the ATF6 serine-rich activation domain.
Figure 5: Activated TAK1 produces cardiac hypertrophy in vivo, with early mortality.
Figure 6: Characterization of the TAK1 phenotype.

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Acknowledgements

We thank B. Boerwinkle, T. Pham and F. Ervin for technical assistance; P. Davies and G. Shipley for access to instrumentation for real-time RT–PCR, M. Abdellatif and R. MacLellan for comments, and R. Roberts for encouragement and support. A.Z. was a PhD candidate in the DeBakey Heart Center Graduate Program in Cardiovascular Sciences. This work was supported in part by grants from the National Institutes of Health, the National Aeronautics and Space Administration, and the Dunn Foundation to M.D.S.

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Authors and Affiliations

  1. The Center for Cardiovascular Development, Baylor College of Medicine, Houston, 77030, Texas, USA

    Dou Zhang, Vinciane Gaussin & Michael D. Schneider

  2. The DeBakey Heart Center Graduate Program in Cardiovascular Sciences, Baylor College of Medicine, Houston, 77030, Texas , USA

    Dou Zhang, George E. Taffet, Robert J. Schwartz, Lloyd H. Michael & Michael D. Schneider

  3. Department of Medicine, Baylor College of Medicine, Houston, 77030, Texas, USA

    Dou Zhang, Vinciane Gaussin, George E. Taffet, Lloyd H. Michael & Michael D. Schneider

  4. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Narasimhaswamy S. Belaguli, Miho Yamada, Robert J. Schwartz, Paul A. Overbeek & Michael D. Schneider

  5. Department of Molecular Physiology & Biophysics Baylor College of Medicine, Houston, 77030, Texas, USA

    Lloyd H. Michael & Michael D. Schneider

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  1. Dou Zhang
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Zhang, D., Gaussin, V., Taffet, G. et al. TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice. Nat Med 6, 556–563 (2000). https://doi.org/10.1038/75037

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