A20 functions as mediator in TNF alpha-induced injury of human umbilical vein endothelial cells through TAK1-dependent MAPK/eNOS pathway

作者：Li, Lei^*; Huang, Bingqing; Song, Shiyang; Sohun, Hareshwaree; Rao, Zhiheng; Tao, Luyuan; Jin, Qike; Zeng, Jingjing; Wu, Rongzhou; Ji, Kangting; Lin, Jiafeng; Wu, Lianpin^*; Chu, Maoping^*

来源：Oncotarget, 2017, 8(39): 65230-65239.

DOI：10.18632/oncotarget.18191

• TNF alpha
• TAK1
• eNOS
• A20
• HUVECs

A20, a negative regulator of nuclear factor kappa B signaling, has been shown to attenuate atherosclerotic events. Transforming growth factor beta-activated kinase 1 (TAK1) plays a critical role in TNF alpha-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 TNF alpha through modulating eNOS activity and TAK1 signalling. Human umbilical vein endothelial cells (HUVECs) were stimulated by TNF alpha. 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 TNF alpha 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, TNF alpha-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.

• 出版日期2017-9-12
• 单位温州医科大学