Low shear stress (LSS) plays a critical role in the development of atherosclerotic plaques and vascular inflammation. Previous studies have reported Akt phosphorylation induced by LSS. However, the mechanism and role of Akt activation remains unclear in LSS-induced endothelial dysfunction. In this study, our results demonstrated the increased phosphorylation of IKKε, TBK1 and Akt in HUVECs exposed to LSS. Furthermore, IKKε silencing using small interfering RNAs significantly reduced LSS-induced Akt phosphorylation. In contrast, silencing of TBK1 or inhibition of PI3K and mTORC2 had no effect on LSS-induced Akt phosphorylation. Notably, Akt inhibition markedly diminished LSS-induced expression of ICAM-1, VCAM-1 and MCP-1, as well as LSS-induced IRF3 phosphorylation and nuclear translocation, without affecting the activation of NF-κB and STAT1. Moreover, endothelial cell specific Akt overexpression mediated by adeno-associated virus markedly increased intimal ICAM-1 and IRF3 expression at LSS area of partially ligated carotid artery in mice. In brief, our findings suggest that LSS-induced Akt phosphorylation is positively regulated by IKKε and promotes IRF3 activation, leading to endothelial inflammation.

低剪切应力 (LSS) 在动脉粥样硬化斑块和血管炎症的发展中起关键作用。以前的研究报道了 LSS 诱导的 Akt 磷酸化。然而，Akt 激活在 LSS 诱导的内皮功能障碍中的机制和作用仍不清楚。在这项研究中，我们的结果表明暴露于 LSS 的 HUVEC 中 IKKε、TBK1 和 Akt 的磷酸化增加。此外，使用小干扰 RNA 进行 IKKε 沉默显着降低了 LSS 诱导的 Akt 磷酸化。相反，TBK1 的沉默或 PI3K 和 mTORC2 的抑制对 LSS 诱导的 Akt 磷酸化没有影响。值得注意的是，Akt 抑制显着降低了 LSS 诱导的 ICAM-1、VCAM-1 和 MCP-1 的表达，以及 LSS 诱导的 IRF3 磷酸化和核转位，而不影响 NF-κB 和 STAT1 的激活。此外，腺相关病毒介导的内皮细胞特异性 Akt 过表达显着增加了小鼠部分结扎的颈动脉 LSS 区域内膜 ICAM-1 和 IRF3 的表达。简而言之，我们的研究结果表明 LSS 诱导的 Akt 磷酸化受 IKKε 的正向调节并促进 IRF3 激活，从而导致内皮炎症。