Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway

• Published in: European journal of pharmacology 2015-05, Vol.754, p.41-51
• Main Authors: Zhang, Ying, Zhan, Ri-Xin, Chen, Jun-Qun, Gao, Yan, Chen, Li, Kong, Ying, Zhong, Xiao-Juan, Liu, Mei-Qi, Chu, Jia-Jia, Yan, Guo-Qiang, Li, Teng, He, Ming, Huang, Qi-Ren
• Format: Article
• Language: English
• Subjects: Animals; Cytokines - metabolism; Diabetes; Down-Regulation - physiology; Endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Human Umbilical Vein Endothelial Cells; Humans; I-kappa B Kinase - metabolism; I-kappa B Proteins - metabolism; Inflammation; Insulin resistance; Insulin Resistance - physiology; Male; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase Type III - metabolism; Peroxisome proliferator-activated receptor gamma; PPAR gamma - agonists; PPAR gamma - physiology; Rats; Repression, Psychology; Signal Transduction - drug effects; Thiazolidinedione; Thiazolidinediones - pharmacology
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.02.004

Vascular endothelial insulin resistance (IR) is a critically initial factor in cardiocerebrovascular events resulted from diabetes and is becoming a worldwide public health issue. Thiazolidinediones (TZDs) are clinical insulin-sensitizers acting through a canonical peroxisome proliferator-activated receptor gamma (PPARγ)-dependent insulin trans-activation pathway. However, it remains elusive whether there are other mechanisms. In current study, we investigated whether TZDs improve endothelial IR induced by high glucose concentration or hyperglycemia via a non-canonical PPARγ-dependent nuclear factor-kappa B (NF-κB) trans-repression pathway. Our results showed that pre-treatment with TZDs dramatically decrease the susceptibility of endothelial cell to IR, while post-treatment notably improve the endothelial IR both in vitro and in vivo. Moreover, TZDs substantially increase the levels of endothelial nitric oxide synthase (eNOS) and inhibitory κB alpha (IκBα), whereas decrease those of the phosphorylated inhibitory κB kinase alpha/beta (phosphor-IKKα/β) and the cytokines including tumor necrosis factor alpha (TNFα), interleukin-6 (IL-6), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cellular adhesion molecule-1 (sVCAM-1), suggesting that TZDs act indeed through a PPARγ-dependent NF-κB trans-repression pathway. These findings highlighted a non-canonical mechanism for TZDs to ameliorate endothelial IR which might provide a potential strategy to prevent and treat the diabetic vascular complications clinically. [Display omitted]