A20 functions as mediator in TNFα-induced injury of human umbilical vein endothelial cells through TAK1-dependent MAPK/eNOS pathway.
A20 functions as mediator in TNFα-induced injury of human umbilical vein endothelial cells through TAK1-dependent MAPK/eNOS pathway.
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A20 通过 TAK1 依赖的 MAPK/eNOS 途径作为 TNF α 诱导的人脐静脉内皮细胞损伤的介质
DOI：
10.18632/oncotarget.18191
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发表时间：
2017-09-12
期刊：
影响因子：
--
通讯作者：
Chu M
中科院分区：
文献类型：
--
作者：
Li L;Huang B;Song S;Sohun H;Rao Z;Tao L;Jin Q;Zeng J;Wu R;Ji K;Lin J;Wu L;Chu M
A20是核因子κB信号的负调控因子，已被证明可以减弱动脉粥样硬化事件。转化生长因子β激活激酶1通过内皮型一氧化氮合酶(ENOS)解偶联和NO还原在肿瘤坏死因子α诱导的动脉粥样硬化中发挥重要作用。在本研究中，我们研究了A20通过调节eNOS活性和Tak1信号通路来保护肿瘤坏死因子α诱导的内皮细胞损伤的假说。用肿瘤坏死因子α刺激人脐静脉内皮细胞。检测A20对细胞凋亡、eNOS表达、NO生成及相关的TAK1信号通路的影响。ENOS和NO的生成量均显著减少。α刺激人脐静脉内皮细胞2小时后，Tak1、p38MAPK的磷酸化增强，HUVECs凋亡增加。抑制A20可显著激活TAK1、p38MAPK的磷酸化，促进细胞凋亡，但抑制eNOS的表达和NO的产生。此外，p38MAPK的表达被A20过表达抑制，但通过抑制A20或激活TAK1而重新增强。此外，通过沉默p38MAPK，可在很大程度上阻止肿瘤坏死因子α对eNOS和NO产生的抑制。综上所述，我们的结果表明，A20介导的TAK1失活抑制了p38MAPK，并调节了MAPK/eNOS通路，这有助于内皮细胞的生存和功能保护。
A20, a negative regulator of nuclear factor κB signaling, has been shown to attenuate atherosclerotic events. Transforming growth factor beta-activated kinase 1 (TAK1) plays a critical role in TNFα-induced atherosclerosis via endothelial nitric oxide (NO) synthase (eNOS) uncoupling and NO reduction. In the study, we investigated the hypothesis that A20 protected endothelial cell injury induced by TNFα through modulating eNOS activity and TAK1 signalling. Human umbilical vein endothelial cells (HUVECs) were stimulated by TNFα. The impact of A20 on cell apoptosis, eNOS expression and NO production and related TAK1 pathway were detected. Both eNOS and NO production were remarkably reduced. TAK1, p38 MAPK phosphorylation and HUVECs apoptosis were enhanced after TNFα stimulation for 2 hrs. Inhibition of A20 significantly activated TAK1, p38 MAPK phosphorylation, and cell apoptosis, but blocked eNOS expression and NO production. Furthermore, p38 MAPK expression was suppressed by A20 over-expression, but re-enhanced by inhibiting A20 or activation of TAK1. Furtherly, TNFα-induced suppression of eNOS and NO production were largely prevented by silencing p38 MAPK. Collectively, our results suggested that A20-mediated TAK1 inactivation suppresses p38 MAPK and regulated MAPK/eNOS pathway, which contributes to endothelial cell survival and function preservation.
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影响因子：
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