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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.

In the present study we determined the long-term effects of persistent, local insulin-like growth factor I (IGF-I) expression on cardiac function in the SIS2 transgenic mouse. Cardiac mass/tibial length was increased in SIS2 mice by 10 wk of age; this cardiac hypertrophy became more pronounced later in life. Peak aortic outflow velocity, a correlate of cardiac output, was increased at 10 wk in SIS2 mice but was decreased at 52 wk. 72 wk SIS2 mouse hearts exhibited wide variability in the extent of cardiac hypertrophy and enlargement of individual cardiac myofibers. Sirius red staining revealed increased fibrosis in 72 wk SIS2 hearts. Persistent local IGF-I expression is sufficient to initially induce an analog of physiological cardiac hypertrophy in which peak aortic outflow velocity is increased relative to controls in the absence of any observed detrimental histological changes. However, this hypertrophy progresses to a pathological condition characterized by decreased systolic performance and increased fibrosis. Our results confirm the short-term systolic performance benefit of increased IGF-I, but our demonstration that IGF-I ultimately diminishes systolic performance raises doubt about the therapeutic value of chronic IGF-I administration. Considering these findings, limiting temporal exposure to IGF-I seems the most likely means of delivering IGF-I's potential benefits while avoiding its deleterious side effects.