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 PPAR gamma-dependent-NF kappa B trans-repression mechanism. However, it is unclear, whether changes in PPAR gamma 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 PPAR gamma-overexpressing (Ad-PPAR gamma) or PPAR gamma-shRNA-containing (Ad-PPAR gamma-shRNA) adenoviral vectors. Likewise, the rats fed by high-fat diet (HFD) were infected by intravenous administration of Ad-PPAR gamma or Ad-PPAR gamma-shRNA. The levels of nitric oxide (NO), endothelin-1 (ET-1) and cytokines (TNF alpha, IL-6, sICAM-1 and sVCAM-1) and the expression levels of PPAR gamma, eNOS, AKT, p-AKT, IKK alpha/beta and p-IKK alpha/beta and I kappa B alpha were examined; and the interaction between PPAR gamma and NF kappa B-P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPAR gamma notably increased the levels of NO, eNOS, p-AKT and I kappa B alpha as well as the interaction of PPAR gamma and NF kappa B-P65, and decreased the levels of ET-1, p-IKK alpha/beta, TNF alpha, IL-6, sICAM-1 and sVCAM-1. In contrast, down-expression of PPAR gamma displayed the opposite effects. The results demonstrate that the overexpression of PPAR gamma improves while the down-expression worsens the endothelium IR via a PPAR gamma-mediated NF kappa B trans-repression dependent manner. The findings suggest PPAR gamma is a potential therapeutic target for diabetic vascular complications.