GW0742对高糖损伤大鼠胸主动脉内皮的保护作用  

Effect of GW0742 on endothelial dysfunction induced by high glucose in isolated rat thoracic aorta

作　　者：薛莱[1] 吴阳[1] 黄波[2] 李荣 蒋青松[1] 

机构地区：[1]重庆医科大学药理学教研室重庆市生物化学与分子药理学重点实验室,重庆400016 [2]遵义医学院药理教研室基础药理省部共建教育部重点实验室,贵州遵义563000 [3]重庆科瑞制药(集团)有限公司,重庆400060

出　　处：《中国药理学通报》2015年第12期1675-1681,共7页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金资助项目(NO 81100905)

摘　　要：目的探讨GW0742对高糖损伤大鼠胸主动脉内皮的作用及可能机制。方法葡萄糖55 mmol·L^(-1)(high glucose,HG)孵育大鼠胸主动脉,以乙酰胆碱(acetylcholine,ACh)诱导的内皮依赖性舒张作用为内皮功能完整性指标,HE染色观察血管形态结构变化,硝酸还原法测量血管内一氧化氮(nitric oxide,NO)含量,利用q RT-PCR和Western blot方法检测血管中过氧化物酶增殖物激活受体β(peroxisome proliferator-activated receptorβ,PPARβ)、核转录因子κB(nuclear transcription factor-κB,NF-κB)及内皮型一氧化氮合酶(endothelial nitric oxide synthase,e NOS)m RNA和蛋白表达。结果 HG条件下,ACh的内皮依赖性舒张作用明显减弱(P<0.01),内皮功能受损;血管内皮细胞和平滑肌细胞结构完整性也被破坏;同时,PPARβm RNA和蛋白表达明显降低(P<0.01),而NF-κB p65的表达则升高(P<0.01),e NOS的表达下降(P<0.01),血管内NO含量亦减少(P<0.01);GW0742(0.01、0.1、1μmol·L~(^(-1)))能剂量依赖性地改善高糖损伤的ACh内皮依赖性舒张作用(P<0.01),减轻内皮细胞和平滑肌细胞的损伤,上调PPARβ表达,减少NF-κB p65的表达,增加e NOS表达和NO的浓度(P<0.01)。结论 GW0742对高糖损伤的大鼠胸主动脉内皮有保护作用,该作用可能与其激活PPARβ,下调NF-κB,改善e NOSNO系统有关。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 performed in the absence or presence of GW0742 at different concentrations under high glucose condition. The structure of aorta was observed by HE staining. Moreover,the content of NO was also measured by nitrate reduction method. The mR NA and protein expression were detected by quantitative real-time PCR and Western 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 interrupted. Furthermore, the expressions of PPARβmR NA and protein reduced while the NF-κB p65 expression increased significantly which occurred in parallel with decreasing e NOS expression and NO concentration( P < 0. 01). GW0742( 0. 01,0. 1,1 μmol·L^(-1)) restored the relaxation of acetylcholine in a dosedependent manner,and reversed the mR NA and protein expression of PPARβ,NF-κB p65 and e NOS,as well as NO content( P < 0. 01). Conclusion GW0742 attenuates the injury of endothelial dysfunction 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 e NOS-NO signal pathway.

关 键 词：GW0742 高糖 内皮损伤 PPARβ NF-κB ENOS NO 

分 类 号：R-332[医药卫生] R322.121