GLP-1受体激动剂对糖尿病动脉粥样硬化大鼠microRNA-155及Toll样受体4表达的影响

Effects of GLP-1R Agonist on the miR-155 Levels and the Expression of TLR4 in Diabetic Atherosclerosis Rats

目的:观察GLP-1受体激动剂(利拉鲁肽)对糖尿病大鼠microRNA-155(miR-155)及Toll样受体4(TLR4)表达的影响。方法:取8周龄雄性SD大鼠40只,适应性喂养1周后随机分为对照组(n=10)和高脂饮食组(n=30),6周后,高脂饮食组大鼠给予STZ诱导2型糖尿病动脉粥样硬化模型,对照组给予等量柠檬酸缓冲液。模型大鼠随机分为糖尿病组、利拉鲁肽中剂量组[200μg/(kg·d)]和利拉鲁肽大剂量组[400μg/(kg·d)],各组10只,干预8周。取血用于测定空腹血糖(FBG),总胆固醇(TC),甘油三酯(TG),低密度脂蛋白胆固醇(LDL-C);RT-PCR法检测各组大鼠主动脉粥样硬化病变部位miR-155、TLR4和核因子-κB(NF-κB)mRNA的水平。结果:与对照组相比,糖尿病组大鼠FBG、TC、TG、LDL-C水平均升高(P<0.01),体重下降(P<0.01);miR-155、TLR4和NF-κB mRNA水平升高(P<0.01)。与糖尿病组相比,利拉鲁肽中、大剂量组血糖、血脂均显著减低(P<0.05);miR-155和TLR4、NF-κB mRNA水平明显下降(P<0.05和P<0.01),其中在利拉鲁肽大剂量组对三者的下调作用更显著。结论:GLP-1受体激动剂不仅显著降低血糖,调节血脂,还能下调动脉粥样硬化病变部位miR-155水平,呈剂量依赖性抑制TLR4/NF-κB炎症因子表达,发挥血管保护作用。

Objective:To observe the effects of liraglutide on the miR-155 levels and the expression of TLR4 in diabetic atherosclerosis rats.Methods:Forty SD rats were randomly divided into the control group(NC,n=10)and the high-fat diet group(HFD,n=30)after one week of adaptive feeding.Six weeks later,rats in HFD group were given streptozotocin to induce type 2 diabetes model.Then,the model rats were randomly divided into the diabetes group(DM),the middle dose of liraglutide group[M-Lir,200μg/(kg·d)]and the high dose of liraglutide group[H-Lir,400μg/(kg·d)].After 8 weeks of intervention,the thoracic aorta and blood samples were collected.Serum fasting blood glucose(FBG)and total cholesterol(TC),triglyceride(TG),low-density lipoprotein-cholesterol(LDL-C)levels were measured.Quantitative real-time PCR was performed to detect the relative expression of miR-155,TLR4 and NF-κB mRNA in the thoracic aorta.Results:Compared with NC group,FBG and TC,TG,LDL-C were increased in DM group(P<0.01),and body weight was decreased(P<0.01),Moreover,miR-155,TLR4 and NF-κB mRNA were increased in DM group than NC group(P<0.01).Compared with DM group,the FBG and TC,TG,LDL-C levels were significantly reduced in M-Lir and H-Lir groups(P<0.05).Futhermore,Liraglutide treatment reduced miR-155 levels and inhibited the expression of TLR4 and NF-κB mRNA(P<0.05 and P<0.01),and these three factors were downregulated more significantly in H-Lri group.Conclusion:GLP-1 R agonist down-regulated the miR-155 levels,and suppressed the expression of TLR4/NF-κB inflammatory pathway in a dose dependent manner.