Trans-repression of NFκB pathway mediated by PPARγ improves vascular endothelium insulin resistance.

Previous study has shown that thiazolidinediones (TZDs) improved endothelium insulin resistance (IR) induced by high glucose concentration (HG)/hyperglycaemia through a PPARγ-dependent-NFκB trans-repression mechanism. However, it is unclear, whether changes in PPARγ expression affect the endothelium IR and what the underlying mechanism is. In the present study, we aimed to address this issue. HG-treated human umbilical vascular endothelial cells (HUVEC) were transfected by either PPARγ-overexpressing (Ad-PPARγ) or PPARγ-shRNA-containing (Ad-PPARγ-shRNA) adenoviral vectors. Likewise, the rats fed by high-fat diet (HFD) were infected by intravenous administration of Ad-PPARγ or Ad-PPARγ-shRNA. The levels of nitric oxide (NO), endothelin-1 (ET-1) and cytokines (TNFα, IL-6, sICAM-1 and sVCAM-1) and the expression levels of PPARγ, eNOS, AKT, p-AKT, IKKα/β and p-IKKα/β and IκBα were examined; and the interaction between PPARγ and NFκB-P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPARγ notably increased the levels of NO, eNOS, p-AKT and IκBα as well as the interaction of PPARγ and NFκB-P65, and decreased the levels of ET-1, p-IKKα/β, TNFα, IL-6, sICAM-1 and sVCAM-1. In contrast, down-expression of PPARγ displayed the opposite effects. The results demonstrate that the overexpression of PPARγ improves while the down-expression worsens the endothelium IR via a PPARγ-mediated NFκB trans-repression dependent manner. The findings suggest PPARγ is a potential therapeutic target for diabetic vascular complications.