Abstract
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.
Highlights
The major causes of vascular diseases are endothelial injury, which is closely related with the atherosclerosis [1]
A20 mediated endothelial nitric oxide (NO) synthase (eNOS) expression in Human umbilical vein endothelial cells (HUVECs) induced by TNFα
Our data showed that nitric oxide (NO) release induced by TNFα was time-dependently reduced, and A20-mediated NO production was largely dependent on the phosphorylation of eNOS
Summary
The major causes of vascular diseases are endothelial injury, which is closely related with the atherosclerosis [1]. Endothelium derived nitric oxide (NO), a vasodilator molecule produced by the intact endothelial layer of the vascular wall, has a key role in vascular biology, functioning as an important regulator of vascular tone, leukocyte adhesion to microvascular endothelium, and capillary leakage [2,3,4]. Exposure to oxidative stress and inflammation induces the endothelium vasodilatation and endothelial cell injury through blocking the generation of eNOS [6]. A20 effectively suppressed inflammatory, vascular injury, cell apoptosis and atherosclerosis formation. Plenty of studies demonstrated that A20 ameliorated endothelial injury through directly upregulating eNOS expression and NO generation [12,13], but the molecular mechanism was undetermined
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