Cardioprotection afforded by NF-kappaB ablation is associated with activation of Akt in mice overexpressing TNF-alpha.
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.
Higuchi
Yoshihiro
Y
Center for Translational Medicine, Dept. of Medicine, Jefferson Medical College, Philadelphia, PA 19107, USA.
Chan
Tung O
TO
Brown
Maria A
MA
Zhang
Jin
J
DeGeorge
Brent R
BR
Funakoshi
Hajime
H
Gibson
Gregory
G
McTiernan
Charles F
CF
Kubota
Toru
T
Jones
W Keith
WK
Feldman
Arthur M
AM
D000818:Animals; D002316:Cardiotonic Agents / Q000378:metabolism*; D005799:Genes, Dominant; D020672:I-kappa B Proteins / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D002316:Cardiotonic Agents; D020672:I-kappa B Proteins; D007328:Insulin; D016328:NF-kappa B; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D051057:Proto-Oncogene Proteins c-akt