1. Academic Validation
  2. Akt phosphorylation regulated by IKKε in response to low shear stress leads to endothelial inflammation via activating IRF3

Akt phosphorylation regulated by IKKε in response to low shear stress leads to endothelial inflammation via activating IRF3

  • Cell Signal. 2021 Apr;80:109900. doi: 10.1016/j.cellsig.2020.109900.
Linlin Zhu 1 Hongfeng Yang 2 Yuelin Chao 3 Yue Gu 3 Junxia Zhang 3 Feng Wang 3 Wande Yu 3 Peng Ye 3 Peng Chu 3 Xiangquan Kong 3 Shaoliang Chen 4
Affiliations

Affiliations

  • 1 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: zhulinlin_007@sina.com.
  • 2 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China; Department of Intensive Care Unit, the Affiliated People(')s Hospital of Jiangsu University, Zhenjiang, China.
  • 3 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China.
  • 4 Department of Cardiology, Nanjing First Hospital, Nanjing Medical University, Nanjing, China. Electronic address: chmengx@126.com.
Abstract

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.

Keywords

Endothelial inflammation; IKKε; Intercellular adhesion molecule-1; Interferon regulatory factor-3; Low shear stress; Protein kinase B (Akt).

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