Sumoylation of peroxisome proliferator-activated receptor γ (PPARγ) affects its stabilization, sublocalization, and transcriptional activity. However, it remains largely unknown whether PPARγ sumoylation inhibits the transactivation effect, leading to endothelium insulin resistance (IR). To test this possibility, human umbilical vascular endothelial cells (HUVECs) with a 90% confluence were randomly allocated to two batches. One batch was first pretreated with or without vitamin E for 24 hr and the other infected with adenoviruses containing either PIAS1-shRNA (protein inhibitor of activated STAT1-short hairpin RNA) or scramble shRNA. Cells were suffered from high glucose and palmitic acid (PA) exposure for further 48 hr. The levels of PPARγ, p-IKK, IKK, and NcoR (nuclear corepressors) were measured by western blot analysis.The interaction of IKK and PIAS1, as well as the PPARγ sumoylation, were examined by coimmunoprecipitation. The results showed that the exposure of high glucose and PA induced reactive oxygen species (ROS) production and IKK activation in HUVECs, promoting the interaction of IKK and PIAS1 and the sumoylation of PPARγ. However, vitamin E and PIAS1-shRNA partially decreased ROS production and IKK activation induced by high glucose and PA exposure. These data indicate that ROS-IKK-PIAS1 pathway mediates PPARγ sumoylation, leading to endothelium IR via stabilizing PPARγ-NcoR complex. These findings benefit understanding of regulatory networks of insulin signaling, which might provide a potential target to prevent and cure IRrelated diseases.
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.
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