TY - JOUR
T1 - TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice
AU - Zhang, Dou
AU - Gaussin, Vinciane
AU - Taffet, George
AU - Belaguli, Narasimhaswamy S.
AU - Yamada, Miho
AU - Schwartz, Robert J.
AU - Michael, Lloyd H.
AU - Overbeek, Paul A.
AU - Schneider, Michael D.
N1 - Funding Information:
Acknowledgments 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.
Copyright:
Copyright 2007 Elsevier B.V., All rights reserved.
PY - 2000/5
Y1 - 2000/5
N2 - 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.
AB - 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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U2 - 10.1038/75037
DO - 10.1038/75037
M3 - Article
C2 - 10802712
AN - SCOPUS:0034105968
VL - 6
SP - 556
EP - 563
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 5
ER -