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

Dou Zhang, Vinciane Gaussin, George Taffet, Narasimhaswamy S. Belaguli, Miho Yamada, Robert J. Schwartz, Lloyd H. Michael, Paul A. Overbeek, Michael D. Schneider

Research output: Contribution to journalArticlepeer-review

276 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)556-563
Number of pages8
JournalNature Medicine
Volume6
Issue number5
DOIs
StatePublished - May 2000

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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