前蛋白转化酶枯草溶菌素9抑制剂作为一级预防治疗对兔动脉粥样硬化斑块发生与进展的影响

Effect of proprotein convertase subtilisin/Kexin type 9 inhibitor as a primary preventive treatment on the occurrence and progression of atherosclerotic plaque in rabbits

目的探讨前蛋白转化酶枯草溶菌素9抑制剂作为一级预防治疗对兔动脉粥样硬化斑块发生与进展的影响。方法选取健康纯种雄性新西兰白兔30只,随机分为对照组、模型组和依洛尤单抗组,每组10只。对照组普通饲料喂养;模型组给予高脂饲料喂养并对右颈动脉内膜进行损伤。依洛尤单抗组在模型组基础上给予依洛尤单抗皮下注射。采集兔外周血,检测各组血脂水平。比较各组血管病理切片。采用免疫组织化学染色法评估CD68、CD147、基质金属蛋白酶9在斑块内的表达。结果模型组、依洛尤单抗组在高脂饮食13周后低密度脂蛋白胆固醇、总胆固醇、甘油三酯水平均高于干预前,且均高于对照组;模型组低密度脂蛋白胆固醇、总胆固醇、甘油三酯水平均高于依洛尤单抗组[(19.1±1.6)mmol/L比(11.2±1.3)mmol/L,(22.2±2.4)mmol/L比(13.1±2.7)mmol/L,(5.8±0.9)mmol/L比(4.7±0.5)mmol/L],差异均有统计学意义(均P<0.05)。对照组未见斑块形成,而模型组和依洛尤单抗组均可见颈动脉斑块形成,模型组斑块内膜巨噬细胞及泡沫细胞丰富,斑块内部可见较大脂质核心,纤维帽薄,形成典型的易损斑块;依洛尤单抗组多表现为内膜增生,较模型组斑块体积及狭窄程度较小,同时CD147、基质金属蛋白酶9表达较模型组少。结论依洛尤单抗的早期干预治疗,可有效控制低密度脂蛋白胆固醇、总胆固醇、甘油三酯水平,显著减小动脉粥样硬化斑块体积及狭窄程度,减轻斑块内脂质沉积,降低炎症反应,使斑块更加稳定,在冠状动脉粥样硬化性心脏病的形成中有着一级预防治疗的意义。

Objective To investigate the effect of proprotein convertase subtilisin/Kexin type 9 inhibitor as primary preventive treatment on the occurrence and progression of atherosclerotic plaque in rabbits.Methods Thirty healthy male New Zealand white rabbits were selected and randomly divided into control group,model group and evolocumab group,with 10 rabbits in each group.The control group was fed with normal diet.The model group was fed with high-fat diet and the right carotid artery intima was injured.The evolocumab group was given subcutaneous injection of evolocumab on the basis of the model group.The peripheral blood of rabbits was collected to detect the lipid levels in each group.The pathological sections of blood vessels in each group were compared.Immunohistochemical staining was used to evaluate the expression of CD68,CD147 and matrix metalloproteinase 9 in the plaques.Results After 13 weeks of high-fat diet,the levels of low-density lipoprotein cholesterol,total cholesterol,and triglyceride in the model group and evolocumab group were higher than those before intervention,and were higher than those in the control group.The levels of low-density lipoprotein cholesterol,total cholesterol,and triglyceride in the model group were higher than those in the evolocumab group[(19.1±1.6)mmol/L vs(11.2±1.3)mmol/L,(22.2±2.4)mmol/L vs(13.1±2.7)mmol/L,(5.8±0.9)mmol/L vs(4.7±0.5)mmol/L](all P<0.05).There was no plaque formation in the control group,while carotid plaque formation was observed in the model group and the evolocumab group.Macrophages and foam cells were abundant in the intima of the plaque in the model group,large lipid core was seen in the plaque,and the fibrous cap was thin,forming a typical vulnerable plaque.Compared with the model group,the evolocumab group showed more intimal hyperplasia,smaller plaque volume and stenosis,and lower expression of CD147 and matrix metalloproteinase 9.Conclusions The early intervention of evolocumab can effectively control the levels of low-density lipoprotein cholesterol,total cholesterol and triglyceride,significantly reduce the volume of atherosclerotic plaque and the degree of stenosis,reduce the lipid deposition in the plaque,reduce the inflammatory reaction,and make the plaque more stable.It has the significance of primary prevention and treatment in the formation of coronary atherosclerotic heart disease.