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

Area of Science:

• Cardiovascular Biology
• Molecular Medicine
• Endothelial Cell Biology

Background:

• Diabetes-associated atherosclerosis involves endothelial dysfunction and inflammation.
• NF-κB-inducing kinase (NIK) and sine oculis homeobox homolog 1 (SIX1) roles are unclear in this context.

Purpose of the Study:

• To investigate the roles of NIK and SIX1 in high glucose-induced endothelial dysfunction and inflammation.
• To elucidate the NIK-SIX1 signaling axis in diabetes-associated atherosclerosis.

Main Methods:

• Human umbilical vein endothelial cells (HUVECs) exposed to high glucose served as a model.
• NIK and SIX1 were silenced using shRNAs.
• Cell proliferation, migration, and inflammatory markers were assessed using EdU staining, scratch tests, ELISA, and western blotting.

Main Results:

• High glucose impaired HUVEC proliferation and migration, increasing VCAM-1, ICAM-1, IL-1β, IL-6, TNF-α, and MCP-1.
• NIK silencing reversed high glucose-induced endothelial dysfunction.
• SIX1 silencing exacerbated high glucose effects, while NIK silencing downregulated SIX1, activating the NF-κB pathway.

Conclusions:

• The NIK-SIX1 signaling axis is critical in regulating high glucose-induced endothelial dysfunction and inflammation.
• SIX1 may act as an immunological gatekeeper, modulating NIK-driven inflammation in diabetic atherosclerosis.