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Cardioprotection afforded by NF-B ablation is associated with activation of Akt in mice overexpressing TNF-

¹Center For Translational Medicine, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania; ²Department of Pharmacology and Cell Biophysics, University of Cincinnati, Cincinnati, Ohio; ³Cardiovascular Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and ⁴Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan

Submitted 18 April 2005 ; accepted in final form 15 September 2005

When selectively overexpressed in mouse heart, TNF- effects the development of a cardiomyopathy that closely mimics that seen in human failing hearts. It has been suggested that two intracellular signaling pathways, the Akt protein kinase and the NF-B transcription factor, mediated TNF- signaling. The present experiments assessed the effects of TNF- overexpression on these two target proteins in vivo. We measured cardiac Akt kinase phosphorylation and NF-B activity in mice overexpressing TNF- (TNF1.6). Both basal and insulin-stimulated Akt phosphorylation were reduced by almost 70% by TNF- overexpression. By contrast, NF-B was robustly activated. These effects were absent when TNF- receptor 1 (TNFR1) was selectively ablated. Cardiomyocyte-specific overexpression of the dominant-negative inhibitory B protein transgene and subsequent inhibition of NF-B activity attenuated the effects of TNF- on Akt phosphorylation. NF-B inhibition also significantly improved fractional shortening and diminished ventricular hypertrophy and survival without affecting infiltrative inflammation or cytokine expression. Thus, while overexpression 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.

tumor necrosis factor-; insulin signaling; TNF- receptor; protein kinase B; dominant-negative inhibitory B protein transgene

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