When selectively overexpressed in mouse heart, TNF-alpha 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-kappaB transcription factor, mediated TNF-alpha signaling. The present experiments assessed the effects of TNF-alpha overexpression on these two target proteins in vivo. We measured cardiac Akt kinase phosphorylation and NF-kappaB activity in mice overexpressing TNF-alpha (TNF1.6). Both basal and insulin-stimulated Akt phosphorylation were reduced by almost 70% by TNF-alpha overexpression. By contrast, NF-kappaB was robustly activated. These effects were absent when TNF-alpha receptor 1 (TNFR1) was selectively ablated. Cardiomyocyte-specific overexpression of the dominant-negative inhibitory kappaB protein transgene and subsequent inhibition of NF-kappaB activity attenuated the effects of TNF-alpha on Akt phosphorylation. NF-kappaB inhibition also significantly improved fractional shortening and diminished ventricular hypertrophy and survival without affecting infiltrative inflammation or cytokine expression. Thus, while overexpression of TNF-alpha effected a marked Akt inhibition and NF-kappaB activation in mouse hearts, inhibition of NF-kappaB offered salutary benefits mediated at least in part through activation of Akt.