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B Ablation Is Associated with Activation of Akt In Mice Over-Expressing TNF
1 Medicine, Jefferson Medical College, Philadelphia, pa, USA
2 Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, oh, USA
3 Institute, University of Pittsburgh School of Medicine, Pittsburgh, pa, USA
4 Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Kyushu, Japan
* To whom correspondence should be addressed. E-mail: arthur.feldman{at}jefferson.edu.
When selectively over-expressed in mouse heart, tumor necrosis factor-alpha (TNF
) effects the development of a cardiomyopathy that closely mimics that seen in human failing hearts. It has been suggested that two intracellular signaling pathway, the Akt protein kinase and the NF-
B transcription factor, mediated TNF signaling. The present experiments assessed the effects of TNF over-expression on these two target proteins in vivo. We measured cardiac Akt kinase and NF-B activity in mice over-expressing TNF (TNF1.6). Both basal and insulin-stimulated Akt activity were reduced by almost 70% by TNF over-expression. By contrast, NF-B was robustly activated. These effects were absent when TNF receptor 1 (TNFR1) was selectively ablated. Over-expression of the dominant-negative IkB transgene and subsequent inhibition of NF-B activity attenuated the effects of TNF on Akt phosphorylation. Cardiac NF-B inhibition also significantly improved fractional shortening and diminished ventricular hypertrophy and survival without effecting infiltrative inflammation or cytokine expression. Thus, while over-expression of TNF effected a marked Akt inhibition and NF-B activation in mouse hearts, inhibition of NF-B offered salutary benefits mediated at least in part through activation of Akt.
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