Cardioprotection afforded by NF-κB ablation is associated with activation of Akt in mice overexpressing TNF-α
Cardioprotection afforded by NF-κB ablation is associated with activation of Akt in mice overexpressing TNF-α
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DOI：
10.1152/ajpheart.00379.2005
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发表时间：
2006-02-01
影响因子：
4.8
通讯作者：
Feldman, AM
中科院分区：
文献类型：
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作者：
Higuchi, Y;Chan, TO;Feldman, AM
当在小鼠心脏中选择性过表达时，TNF-α影响心肌病的发展，这与在人类衰竭心脏中看到的非常相似。已经提出两种细胞内信号传导途径，Akt蛋白激酶和NF-κ B转录因子，介导TNF-α信号传导。本实验评估了TNF-α过表达对体内这两种靶蛋白的影响。我们测量了过表达TNF-α（TNF 1.6）小鼠的心脏Akt激酶磷酸化和NF-κ B B活性。基础和胰岛素刺激的Akt磷酸化通过TNF-α过表达降低了近70%。相比之下，NF-κ B被强烈激活。当选择性消融TNF-α受体1（TNFR 1）时，这些作用不存在。心肌细胞特异性过表达显性负抑制性κ B蛋白转基因和随后抑制NF-κ B活性减弱了TNF-α对Akt磷酸化的影响。NF-κ B抑制还显著改善短轴缩短率，降低心室肥大和存活率，而不影响浸润性炎症或细胞因子表达。因此，虽然TNF-α的过表达在小鼠心脏中实现了显著的Akt抑制和NF-κ B活化，但是NF-κ B的抑制提供了有益的益处，其至少部分地通过Akt的活化介导。
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-kappa B 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-kappa B 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-kappa B was robustly activated. These effects were absent when TNF-alpha receptor 1 ( TNFR1) was selectively ablated. Cardiomyocyte-specific overexpression of the dominant-negative inhibitory kappa B protein transgene and subsequent inhibition of NF-kappa B activity attenuated the effects of TNF-alpha on Akt phosphorylation. NF-kappa 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-alpha effected a marked Akt inhibition and NF-kappa B activation in mouse hearts, inhibition of NF-kappa B offered salutary benefits mediated at least in part through activation of Akt.