前蛋白转化酶枯草溶菌素9抑制剂通过降低血管细胞黏附分子-1减缓载脂蛋白E基因敲除小鼠动脉粥样硬化进展  

Inhibitors of proprotein convertase subtilisin/kexin type 9 slow atherosclerosis progression in apolipoprotein E gene knockout mice by decreasing vascular cell adhesion molecule-1

作　　者：郑方芳 邓琴琴 熊芳芳 刘衍冬 ZHENG Fangfang;DENG Qinqin;XIONG Fangfang;LIU Yandong(Department of Cardiology,the Third Hospital of Nanchang,Jiangxi Province,Nanchang 330006,China)

机构地区：[1]南昌市第三医院心内科,江西南昌330006

出　　处：《中国当代医药》2024年第16期20-25,共6页China Modern Medicine

基　　金：江西省卫生健康委科技计划项目(202311257)。

摘　　要：目的探究前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂减缓动脉粥样硬化(AS)的分子机制。方法选取45只载脂蛋白E基因敲除(ApoE^(-/-))小鼠作为研究对象,采用随机数字表法分为对照组、AS模型组和PCSK9抑制剂干预组,每组15只。以普通喂养方式为对照组,通过高脂饮食诱导构建AS模型组,高脂喂养并给予PCSK9抑制剂作为PCSK9抑制剂干预组。实验结束后取小鼠血浆测定血脂浓度;取小鼠主动脉根部,制作切片并通过油红O染色及苏木精-伊红(HE)染色观察AS病理形态学改变;通过免疫组化染色测定主动脉组织血管细胞黏附分子1(VCAM-1)表达;取小鼠胸主动脉利用real-time PCR和Western Blot法测定主动脉血管中VCAM-1的mRNA含量及蛋白表达;ELISA测定血浆肿瘤坏死因子-α(TNF-α)、纤溶酶原激活物抑制物-1(PAI-1)浓度。结果AS模型组小鼠血浆中总胆固醇(TC)、甘油三酯(TG)、低密度脂蛋白胆固醇(LDL-C)水平高于对照组,高密度脂蛋白胆固醇(HDL-C)低于对照组,差异有统计学意义(P<0.05);PCSK9抑制剂干预组血浆TC、TG、LDL-C、HDL-C水平与对照组比较,差异无统计学意义(P>0.05),PCSK9抑制剂干预组血浆TC、TG、LDL-C水平低于AS模型组,HDL-C高于AS模型组,差异有统计学意义(P<0.05)。AS模型组主动脉硬化斑块相对面积大于对照组,而PCSK9抑制剂干预组斑块相对面积小于AS模型组,差异有统计学意义(P<0.05)。AS模型组和PCSK9抑制剂干预组小鼠主动脉VCAM-1蛋白表达及mRNA水平高于对照组,而PCSK9抑制剂干预组VCAM-1蛋白表达及mRNA水低于AS模型组,差异有统计学意义(P<0.05)。AS模型组血浆TNF-α、PAI-1水平高于对照组,而PCSK9抑制剂干预组血浆TNF-α、PAI-1水平低于AS模型组,差异有统计学意义(P<0.05),但PCSK9抑制剂干预组血浆TNF-α、PAI-1含量与对照组比较,差异无统计学意义(P>0.05)。结论PCSK9抑制剂可降低血液中炎症因子TNF-α和PAI-1浓度,从而减少主�Objective To explore the molecular mechanism of proprotein convertase subtilisin/kexin type 9(PCSK9)inhibitors to slow atherosclerosis(AS).Methods A total of 45 apolipoprotein E gene knockout(ApoE^(-/-))mice were selected as the study objects,and they were divided into control group,AS model group and PCSK9 inhibitor intervention group by random number table method,with 15 mice in each group.Mice in control group were fed a normal diet.The AS model group was established by high-fat diet induction,and the PCSK9 inhibitor intervention group was fed high-fat diet and injected with PCSK9 inhibitors.After the end of experiment,plasma of mice was collected to determine the concentration of blood lipids.Aortic roots of mice were sliced and stained with oil red O and hematoxylin-eosin(HE)to observe pathological changes.The expression of VCAM-1 in aortic tissues of mice in each group was detected by immunohistochemical assay.The mRNA content and protein expression of VCAM-1 in thoracic aorta were determined by real-time PCR and Western Blot.The concentrations of plasma tumor necrosis factor-α(TNF-α)and plasminogen activator inhibitor-1(PAI-1)were determined by ELISA.Results After intervention,plasma levels of total cholesterol(TC),triglyceride(TG)and low-density lipoprotein cholesterol(LDL-C)in AS model group were higher than those in control group,the level of high density lipoprotein cholesterol(HDL-C)was lower than that in control group,the differences were statistically significant(P<0.05).There were no significant differences in plasma levels of TC,TG,LDL-C and HDL-C between PCSK9 inhibitor intervention group and control group(P>0.05).The plasma levels of TC,TG and LDL-C in PCSK9 inhibitor intervention group were lower than those in AS model group,and HDL-C was higher than that in AS model group,with statistical significances(P<0.05).The relative area of aortic atherosclerotic plaque in AS model group was larger than that in control group,the relative area of aortic atherosclerotic plaque in PCSK9 inhibitor interve

关 键 词：前蛋白转化酶枯草溶菌素9抑制剂 动脉粥样硬化 血管细胞黏附分子-1 炎症因子 

分 类 号：R543[医药卫生—心血管疾病]