TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice.
The transforming-growth-factor-beta-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 beta. 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.
Zhang
D
D
The Center for Cardiovascular Development, Baylor College of Medicine, Houston, Texas 77030, USA.
Gaussin
V
V
Taffet
G E
GE
Belaguli
N S
NS
Yamada
M
M
Schwartz
R J
RJ
Michael
L H
LH
Overbeek
P A
PA
Schneider
M D
MD
D051702:Activating Transcription Factor 6; D000818:Animals; D001011:Aorta / Q000601:surgery; D001794:Blood Pressure; D002303:Cardiac Output, Low / Q000209:etiology*; D006332:Cardiomegaly / Q000209:etiology*; D004268:DNA-Binding Proteins / Q000378:metabolism; D003971:Diastole; D015536:Down-Regulation; D020930:MAP Kinase Kinase Kinases / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D026362:Serum Response Factor; D015398:Signal Transduction; D013599:Systole; D014157:Transcription Factors; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7
D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D026362:Serum Response Factor; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D048051:p38 Mitogen-Activated Protein Kinases; D000099151:MAP Kinase Kinase Kinase 7; C497112:Atf6 protein, mouse