Protective effects of pioglitazone on vascular endothelial cell dysfunction induced by high glucose via an inhibition of IKKα/β-NFκB signaling mediated by PPARγ in vitro

Pioglitazone (PIO), a synthetic ligand for peroxisome proliferator activated receptor γ (PPARγ), is clinically used to treat type 2 diabetes mellitus. However, little is known on its endothelial protective effects and the underlying mechanisms. In this study, we sought to investigate PIO’s endothelial protective effects and its likely mechanisms. 95% confluent high glucose concentration (HG, 33 mM)-injured WT-HUVECs and PPARγLow-HUVECs were first pretreated with 10 μM of GW9662 for 30 minutes, and then treated with various concentrations of PIO (5, 10, 20 μM) for 24 hours. Finally, the levels of NO, endothelin 1(ET1), tumor necrosis factor alpha (TNFα) and interleukin 6 (IL6) were detected. The cells were utilized to determine the cell viability, caspase3 activity, the levels of inhibitory κB kinase α/β (IKKα/β) mRNA, IKKα/β, and nuclear factor κB (NFκB) p65. Severe dysfunction and activation of IKKα/β-NFκB signaling occurred after exposure of HUVECs to HG. Conversely, treatment with PIO significantly attenuated the dysfunction and the activation of IKKα/β-NFκB signaling induced by HG in a dose-dependent manner. Moreover, the protective effects of PIO were completely abrogated by GW9662 or down-regulation of PPARγ. Taken together, PIO protects HUVECs against the HG-induced dysfunction through the inhibition of IKKα/β-NFκ B signaling mediated by PPARγ.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author