| First Author | Higuchi Y | Year | 2006 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 290 |
| Issue | 2 | Pages | H590-8 |
| PubMed ID | 16199483 | Mgi Jnum | J:106726 |
| Mgi Id | MGI:3619303 | Doi | 10.1152/ajpheart.00379.2005 |
| Citation | Higuchi Y, et al. (2006) Cardioprotection afforded by NF-kappaB ablation is associated with activation of Akt in mice overexpressing TNF-alpha. Am J Physiol Heart Circ Physiol 290(2):H590-8 |
| abstractText | 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. |
