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

Abstract Previous study has shown that thiazolidinediones ( TZD s) improved endothelium insulin resistance ( IR ) induced by high glucose concentration ( HG )/hyperglycaemia through a PPAR γ‐dependent‐ NF κB trans‐repression mechanism. However, it is unclear, whether changes in PPAR γ 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 γ‐overexpressing (Ad‐ PPAR γ) or PPAR γ‐sh RNA ‐containing (Ad‐ PPAR γ‐sh RNA ) adenoviral vectors. Likewise, the rats fed by high‐fat diet ( HFD ) were infected by intravenous administration of Ad‐ PPAR γ or Ad‐ PPAR γ‐sh RNA . The levels of nitric oxide ( NO ), endothelin‐1 ( ET ‐1) and cytokines ( TNF α, IL ‐6, sICAM ‐1 and sVCAM ‐1) and the expression levels of PPAR γ, eNOS , AKT , p‐ AKT , IKK α/β and p‐ IKK α/β and IκBα were examined; and the interaction between PPAR γ and NF κB‐P65 as well as vascular function were evaluated. Our present results showed that overexpression of PPAR γ notably increased the levels of NO , eNOS , p‐ AKT and IκBα as well as the interaction of PPAR γ and NF κB‐P65, and decreased the levels of ET ‐1, p‐ IKK α/β, TNF α, IL ‐6, sICAM ‐1 and sVCAM ‐1. In contrast, down‐expression of PPAR γ displayed the opposite effects. The results demonstrate that the overexpression of PPAR γ improves while the down‐expression worsens the endothelium IR via a PPAR γ‐mediated NF κB trans‐repression dependent manner. The findings suggest PPAR γ is a potential therapeutic target for diabetic vascular complications.