NIK-SIX1 signalling axis regulates high glucose-induced endothelial cell dysfunction and inflammation

Abstract

Endothelial dysfunction and inflammation are the main manifestations of diabetes-associated atherosclerosis. This paper studied the roles of NF-κB-inducing kinase (NIK) and sine oculis homeobox homolog 1 (SIX1) in regulating high glucose-induced endothelial dysfunction and inflammation. The expression of NIK and SIX1 in human umbilical vein endothelial cells (HUVECs) was silenced by transfection with the specific shRNAs. HUVECs exposed to high glucose were considered as a cell model of endothelial dysfunction. Expression of NIK and SIX1 following transfection was measured by qRT-PCR and western blotting analysis. The proliferation, migration, and inflammation of HUVECs were evaluated by EdU staining, scratch test, ELISA, and western blotting. High glucose (30 mM) significantly decreased the proliferation and migration of HUVECs. High glucose-induced the expression of adhesion molecules VCAM-1 and ICAM-1. Moreover, high glucose increased the release of IL-1β, IL-6, TNF-α, and MCP-1. Transfection of cells with NIK shRNA significantly reversed the toxic effects of high glucose on HUVECs. Of contrast, SIX1 shRNA accelerated the effects of high glucose on HUVECs. NIK shRNA inhibited the accumulation of RelA, RelB, and p52. Meanwhile, NIK shRNA led to SIX1 downregulation which further induced the activation of the NF-κB pathway. NIK-SIX1 signalling axis was suggested to be critical in the regulation of high glucose-induced endothelial dysfunction and inflammation. SIX1 may function as an immunological gatekeeper to control the excessive inflammation mediated by NIK in diabetes-associated atherosclerosis.

Keywords:

• Diabetes
• atherosclerosis
• NIK
• SIX1
• NF-κB pathway

Disclosure statement

The authors declare that they have no conflicts of interest.

Author contributions

Bo Li: conception and design. Haiming Li, Longsheng Dai, and Changcheng Liu: perform research. Liangshan Wang, Qin Li, and Chengxiong Gu: data analysis and interpretation. Bo Li: manuscript writing. All authors: final approval of the manuscript.

Data availability statement

The datasets used and analysed during the current study are available from the corresponding author on reasonable request.