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

Abstract

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.

Ginsenoside Rc Ameliorates Endothelial Insulin Resistance via Upregulation of Angiotensin-Converting Enzyme 2

“…Among the molecules secreted by endothelium, NO and ET-1 play a crucial part in modulating vascular tone and vessel integrity stimulated by insulin ( Baratchi et al, 2017 ), which are often chosen as the markers of endothelial IR ( Kearney et al, 2008 ). HG has been widely used to establish endothelial IR model in HUVECs ( Yang et al, 2010 ; Ying et al, 2014 ; Kong et al, 2019 ). In the present study, HG treatment decreased NO content, elevated ET-1 mRNA level, caused significant augment of ROS, and produced impairment in insulin signaling pathway, suggesting a successful IR model in HUVECs.…”

“…Insulin resistance (IR) is usually defined as decreased sensitivity to metabolic actions of insulin in target tissues including muscle, liver, and adipose ( Kim et al, 2006 ; Kong et al, 2019 ) and plays a critical role in the development of type 2 diabetes mellitus (T2DM), which is frequently present in obesity, dyslipidemia, and metabolic syndrome ( DeFronzo and Ferrannini, 1991 ; Petersen et al, 2007 ). In addition to its essential metabolic actions, insulin has important vascular actions mediated by endothelium via insulin signaling pathways ( Baron and Clark, 1997 ).…”

Effect of temperature-sensitive nanogel combined with angioplasty on sICAM-1 and VE-cadherin in lower extremity arterial occlusion rabbits

“…Studies have shown that VE-cadherin can maintain the stability of the internal environment and is instrumental in maintaining the integrity of normal vascular endothelium [ 26 ]. sICAM-1 is a soluble intercellular adhesion molecule, which can reflect the local expression of ICAM-1, and participates in the activation of endothelial cells and signal transduction [ 27 ]. The results of this study showed that the levels of VE-cadherin and sICAM-1 were increased, and the levels of VE-cadherin and sICAM-1 were decreased after SIA.…”