PCSK9抑制剂对动脉粥样硬化小鼠的降脂抗炎治疗研究

Study on lipid-lowering and anti-inflammatory therapy of atherosclerosis mice with PCSK9 inhibitors

目的:探讨PCSK9抑制剂及他汀类药物干预对ApoE^(-/-)动脉粥样硬化小鼠的降脂抗炎治疗效果。方法:选取雄性c57小鼠和c57背景下的ApoE^(-/-)雄性小鼠高脂饮食喂养,构建空白模型及动脉粥样硬化小鼠模型,分别进行阿托伐他汀钙10 mg/kg·d^(-1)灌胃及每1周皮下注射PCSK9抑制剂10 mg/kg一次,观察小鼠活动量、毛发和精神状态。取血后离心出血清,检测外周血中的TC、TG、LDL-C、IL-1、IL-6、IL-12,HE染色分析动脉粥样斑块。结果:他汀组、PCSK9抑制剂组和他汀+PCSK9抑制剂组小鼠对比模型组TG、TC、和LDL-C均降低(P<0.01),IL-1β、IL-6均降低(P<0.01),IL-12均升高(P<0.01);他汀组小鼠较PCSK9抑制剂组TC和TG均升高(P<0.05),较联合用药组TG、TC和LDL-C均升高(P<0.01);PCSK9抑制剂组小鼠较联合用药组TG、TC和LDL-C均升高(P<0.05)。他汀组小鼠较空白组、PCSK9抑制剂组和他汀+PCSK9抑制剂组的IL-β、IL-6均升高(P<0.01),IL-12均降低(P<0.01);病理学观察模型组小鼠脂质浸润较多,炎症增加,他汀组、PCSK9抑制组和他汀组+PCSK9抑制组小鼠较模型组脂质浸润较少,炎症减少。结论:PCSK9抑制剂具有良好的降脂、抗炎效果,与他汀类药物联用效果更佳。

Objective:To observe the effect of PCSK9 inhibitor and statin on lipid-lowering antiinflammatory therapy and biomechanical properties of ApoE^(-/-)atherosclerosis mice.Methods:Male c57 mice and ApoE^(-/-)male mice with c57 background were fed high-fat diet,blank model and atherosclerosis mouse model were constructed,and atorvastatin calcium 10 mg/kg·d^(-1) and PCSK9 inhibitor 10 mg/kg were injected subcutively every week,respectively.The activity,hair and mental state of the mice were observed.After blood collection,serum was centrifuged and TC,TG,LDL-C,IL-1,IL-6 and IL-12 in peripheral blood were detected.Atherosclerotic plaque was analyzed by HE staining.Results:TG,TC,LDL-C were decreased in statin group,PCSK9 inhibitor group and statin+PCSK9 inhibitor group compared with model group(P<0.01).IL-1βand IL-6 were decreased(P<0.01),while IL-12 was increased(P<0.01).Compared with PCSK9 inhibitor group,TC and TG were increased in statin group(P<0.05),and TG,TC and LDL-C were increased in combination group(P<0.01).TG,TC,LDL and LDL-C in PCSK9 inhibitor group were higher than those in combination treatment group(P<0.05).Compared with blank group,PCSK9 inhibitor group and statin+PCSK9 inhibitor group,IL-βand IL-6 were increased(P<0.01),and IL-12 were decreased(P<0.01).Pathological observation:the model group had more lipid infiltration and increased inflammation,and the statin group,PCSK9 inhibition group and statin+PCSK9 inhibition group had less lipid infiltration and decreased inflammation than the model group.Conclusion:PCSK9 inhibitors have good lipid-lowering and antiinflammatory effects,and the combined effect with statins is better.