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

Yoshihiro Higuchi, Tung O. Chan, Maria A. Brown, Jin Zhang, Brent R. DeGeorge, Hajime Funakoshi, Gregory Gibson, Charles F. McTiernan, Toru Kubota, W. Keith Jones, Arthur M. Feldman

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44 Citations (Scopus)

Abstract

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

Original languageEnglish
Pages (from-to)H590-H598
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume290
Issue number2
DOIs
Publication statusPublished - Feb 1 2006
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Higuchi, Y., Chan, T. O., Brown, M. A., Zhang, J., DeGeorge, B. R., Funakoshi, H., Gibson, G., McTiernan, C. F., Kubota, T., Jones, W. K., & Feldman, A. M. (2006). Cardioprotection afforded by NF-κB ablation is associated with activation of Akt in mice overexpressing TNF-α. American Journal of Physiology - Heart and Circulatory Physiology, 290(2), H590-H598. https://doi.org/10.1152/ajpheart.00379.2005