Résumé
Aim To investigate the effect of GW0742 on the endothelial dysfunction induced by high glucose (glucose at 55 mmol · L -1 )in isolated rat thoracic aorta and its related mechanisms.Methods The end othelium-dependent relaxation of acetylcholine was per-formed in the absence or presence of GW0742 at differ-ent concentrations under high glucose condition.The structure of aorta was observed by HE staining.Moreo-ver,the content of NO was also measured by nitrate re-duction method.The mRNA and protein expression were detected by quantitative real-time PCR and West-ern blot,respectively.Results Compared with the control group,acetylcholine-induced vasodilatation was impaired by high glucose.Meanwhile,the structures of endothelial cells and smooth muscle cells were also in-terrupted.Furthermore, the expressions of PPARβmRNA and protein reduced while the NF-κB p65 ex-pression increased significantly which occurred in par- allel with decreasing eNOS expression and NO concen-tration (P <0.01 ).GW0742 (0.01 ,0.1 ,1 μmol· L -1 )restored the relaxation of acetylcholine in a dose-dependent manner,and reversed the mRNA and pro-tein expression of PPARβ,NF-κB p65 and eNOS,as well as NO content (P <0.01 ).Conclusion GW0742 attenuates the injury of endothelial dysfunc-tion induced by high glucose,which may be,at least partly,mediated by the up-regulation of PPARβ,then the down-regulation of NF-κB,and the activation of eNOS-NO signal pathway.
Résumé
Although peroxisome proliferator receptor (PPAR)-alpha and PPAR-gamma agonist have been developed as chemical tools to uncover biological roles for the PPARs such as lipid and carbohydrate metabolism, PPAR-delta has not been fully investigated. In this study, we examined the effects of the PPAR-delta agonist GW0742 on fatty liver changes and inflammatory markers. We investigated the effects of PPAR-delta agonist GW0742 on fatty liver changes in OLETF rats. Intrahepatic triglyceride contents and expression of inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and monocyte chemo-attractant protein-1 (MCP-1) and also, PPAR-gamma coactivator (PGC)-1alpha gene were evaluated in liver tissues of OLETF rats and HepG2 cells after GW0742 treatment. The level of TNF-alpha and MCP-1 was also examined in supernatant of Raw264. 7 cell culture. To address the effects of GW0742 on insulin signaling, we performed in vitro study with AML12 mouse hepatocytes. Rats treated with GW0742 (10 mg/kg/day) from 26 to 36 weeks showed improvement in fatty infiltration of the liver. In liver tissues, mRNA expressions of TNF-alpha, MCP-1, and PGC-1alpha were significantly decreased in diabetic rats treated with GW0742 compared to diabetic control rats. We also observed that GW0742 had inhibitory effects on palmitic acid-induced fatty accumulation and inflammatory markers in HepG2 and Raw264.7 cells. The expression level of Akt and IRS-1 was significantly increased by treatment with GW0742. The PPAR-delta agonist may attenuate hepatic fat accumulation through anti-inflammatory mechanism, reducing hepatic PGC-1alpha gene expression, and improvement of insulin signaling.