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首页> 外文期刊>American Journal of Physiology >Rapamycin antagonizes NF-kappaB nuclear translocation activated by TNF-alpha in primary vascular smooth muscle cells and enhances apoptosis.
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Rapamycin antagonizes NF-kappaB nuclear translocation activated by TNF-alpha in primary vascular smooth muscle cells and enhances apoptosis.

机译：雷帕霉素拮抗由TNF-α激活的原代血管平滑肌细胞中的NF-κB核易位，并增强细胞凋亡。

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摘要

Several lines of evidence support the view that rapamycin inhibits NF-kappaB. TNF-alpha, a potent inducer of NF-kappaB, is released after artery injury (e.g., balloon angioplasty) and plays an important role in inflammation and restenosis. We investigated the effect of rapamycin on NF-kappaB activation and apoptosis in vascular smooth muscle cells (VSMCs) stimulated with TNF-alpha. Using EMSA, we found that TNF-alpha caused NF-kappaB nuclear translocation in VSMCs after 1 h of incubation. Rapamycin inhibited IkappaBalpha degradation, thereby preventing nuclear translocation. Activation of NF-kappaB was accompanied by an increase of Bcl-xL and Bfl-1/A1 proteins, detected by Western blot assay, whereas rapamycin prevented the TNF-alpha-induced enhancement of these antiapoptotic proteins. The extent of apoptosis of VSMCs exposed to TNF-alpha was significantly enhanced by rapamycin. The effect of rapamycin appeared to be independent of the phosphatidylinositol 3-kinase/Akt-protein kinase B survival pathway, because the phosphatidylinositol 3-kinase inhibitor wortmannin neither prevented IkappaBalpha degradation nor increased apoptosis of cells incubated with TNF-alpha. Finally, we demonstrate that the large immunophilin FK-506 binding protein FKBP51 is essential for TNF-alpha-induced NF-kappaB activation in VSMCs. Our findings show that rapamycin inhibits NF-kappaB activation and acts in concert with TNF-alpha in induction of VSMC apoptosis.
机译：有几条证据支持雷帕霉素抑制NF-κB的观点。 TNF-α是一种有效的NF-κB诱导剂，在动脉损伤（例如球囊血管成形术）后释放，并在炎症和再狭窄中起重要作用。我们调查了雷帕霉素对TNF-α刺激的血管平滑肌细胞（VSMC）中NF-κB活化和凋亡的影响。使用EMSA，我们发现在孵育1小时后，TNF-α导致VSMC中的NF-κB核易位。雷帕霉素抑制IkappaBalpha降解，从而防止核易位。蛋白质印迹法检测到，NF-κB的活化伴随着Bcl-xL和Bfl-1 / A1蛋白的增加，而雷帕霉素阻止了TNF-α诱导的这些抗凋亡蛋白的增强。雷帕霉素显着增强了暴露于TNF-α的VSMC的凋亡程度。雷帕霉素的作用似乎与磷脂酰肌醇3-激酶/ Akt-蛋白激酶B的生存途径无关，因为磷脂酰肌醇3-激酶抑制剂渥曼青霉素既不能阻止IkappaBalpha降解，也不能增加与TNF-α孵育的细胞的凋亡。最后，我们证明了大型亲免蛋白FK-506结合蛋白FKBP51对于VSMC中TNF-α诱导的NF-κB活化是必不可少的。我们的发现表明，雷帕霉素可抑制NF-κB活化并与TNF-α协同作用，诱导VSMC凋亡。

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