基于内质网应激探讨GLP-1RA抗动脉粥样硬化的作用  

Anti-atherosclerosis Effects of GLP-1RA by Reducing Endoplasmic Reticulum Stress

作　　者：王珊珊 张敏[1] 刘恒方[1] 丁炫景 张权 王欣格 WANG Shanshan;ZHANG Min;LIU Hengfang(The Third Department of Neurology,The Fifth Affiliated Hospital of Zhengzhou University,Henan 450052,China)

机构地区：[1]郑州大学第五附属医院神经内三科,450052 [2]新乡医学院第三附属医院,453003

出　　处：《医学研究杂志》2023年第10期90-94,135,共6页Journal of Medical Research

基　　金：河南省医学科技攻关计划省部共建项目(SB201901056)。

摘　　要：目的探讨胰高血糖素样肽-1受体激动剂(glucagon-like peptide-1 receptor agonist,GLP-1RA)Exendin-4对载脂蛋白E基因敲除(ApoE-/-)小鼠动脉粥样硬化斑块的作用及内质网应激通路的影响。方法将16只ApoE-/-小鼠随机分为模型组、Exendin-4组,同时以C57BL/6J小鼠作为对照组,8只/组。对照组给予普通饲料,其余组给予高脂饲料喂养12周建立动脉粥样硬化斑块模型,Exendin-4组给予Exendin-4腹腔注射,20μg/(kg·d),余两组分别腹腔注射等量0.9%氯化钠溶液,干预4周。监测各组小鼠血糖变化,给药结束后检测血清总胆固醇、甘油三酯水平,留取主动脉用HE染色、天狼星红染色观察斑块,免疫组化法检测斑块中内质网应激相关蛋白葡萄糖调节蛋白78(glucose-regulated protein 78,GRP78)、C/EBP同源蛋白(C/EBP homologous protein,CHOP)、凋亡蛋白B淋巴细胞瘤-2(apoptotic protein B lymphoblastoma-2,Bcl-2)的表达情况。结果Exendin-4组随机血糖水平与模型组比较差异无统计学意义(P>0.05),Exendin-4组血清TC水平较模型组降低(P<0.05),TG水平比较差异无统计学意义(P>0.05);病理学形态观察显示Exendin-4组主动脉斑块面积较模型组变小,斑块内胶原含量增多,脂质、泡沫细胞数目均减少,管腔狭窄减轻;Exendin-4组GRP78、CHOP阳性细胞数较模型组明显减少(P均<0.05),Bcl-2阳性细胞数增多(P<0.05)。结论GLP-1RA具有改善动脉粥样硬化的作用,其机制可能是通过下调内质网应激,降低凋亡蛋白的表达来实现的。Objective To investigate the effects of glucagon-like peptide-1 receptor agonist(GLP-1RA)exendin-4 on atherosclerotic plaques and endoplasmic reticulum stress pathway proteins in apolipoprotein E gene knockout(ApoE-/-)mice.Methods Sixteen ApoE-/-mice were randomly divided into model group and Exendin-4 group,and C57BL/6J mice were used as control group(n=8).The control group was given ordinary diet,and the other groups were fed with high-fat diet for 12 weeks to establish the atherosclerosis plaque model.The Exendin-4 group was given intraperitoneal injection of the corresponding drug,20μg/(kg·d),and the other two groups were intraperitoneally injected with the same amount of normal saline for 4 weeks.Blood glucose changes of each group were monitored,serum total cholesterol(TC)and triglyceride(TG)levels were detected after administration.The aorta was retained and stained with HE and Sirius red to observe plaques.The expressions of endoplasmic reticulum stress-related protein glucose-regulated protein 78(GRP78),C/EBP homologous protein(CHOP)and apoptotic protein B lymphoblastoma-2(Bcl-2)in atherosclenic plaques were detected by immunohistochemistry.Results There was no significant difference in the random blood glucose level between the Exendin-4 group and the model group(P>0.05),the serum TC level in the Exendin-4 group was lower than that in the model group(P<0.05),and the TG level was not significantly different(P>0.05).Pathological observation showed that the aortic plaque area of Exendin-4 group was smaller than that of model group,the collagen content in the plaque increased,the number of lipid and foam cells decreased,and the degree of lumen stenosis was alleviated.The number of GRP78 and CHOP positive cells in Exendin-4 group was significantly decreased compared with that in model group(P<0.05),and the number of Bcl-2 positive cells was increased(P<0.05).Conclusion GLP-1RA can improve atherosclerosis by down-regulating endoplasmic reticulum stress and reducing the expression of apoptotic proteins.

关 键 词：胰高血糖素样肽-1 动脉粥样硬化 内质网应激 

分 类 号：R543.5[医药卫生—心血管疾病]