title: Pharmacological activation of PPAR gamma ameliorates vascular endothelial insulin resistance via a non-canonical PPAR gamma-dependent nuclear factor-kappa B trans-repression pathway.
abstract: 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.
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Ying
authors: Y
authors: Zhang
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Ri-Xin
authors: RX
authors: Zhan
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Jun-Qun
authors: JQ
authors: Chen
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Yan
authors: Y
authors: Gao
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Li
authors: L
authors: Chen
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Ying
authors: Y
authors: Kong
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Xiao-Juan
authors: XJ
authors: Zhong
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Mei-Qi
authors: MQ
authors: Liu
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Jia-Jia
authors: JJ
authors: Chu
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Guo-Qiang
authors: GQ
authors: Yan
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Teng
authors: T
authors: Li
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China.
authors: Ming
authors: M
authors: He
authors: Jiangxi Provincial Key Laboratory of Basic Pharmacology, Nanchang University, Nanchang 330006, PR China; Department of Pharmacology, Pharmaceutical Science College, Nanchang University, Nanchang 330006, PR China. Electronic address: qrhuang@ncu.edu.cn.
authors: Qi-Ren
authors: QR
authors: Huang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D020672:I-kappa B Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists* / Q000502:physiology*; D051381:Rats; D012094:Repression, Psychology; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000494:pharmacology
chemical_list: D016207:Cytokines; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; C000606206:Nfkbia protein, rat; D047495:PPAR gamma; D045162:Thiazolidinediones; D000072000:NF-KappaB Inhibitor alpha; D052250:Nitric Oxide Synthase Type III; D051550:I-kappa B Kinase
keywords: Diabetes; Endothelium; Inflammation; Insulin resistance; Peroxisome proliferator-activated receptor gamma; Thiazolidinedione