目的 探讨地奥心血康 （以下简称心血康） 联合辛伐他汀对动脉粥样硬化 （AS） 小鼠的影响及机制。方法 将 8 只 C57BL/6J 小鼠作为对照组，将 32 只 ApoE-/- 小鼠随机分为模型组、心血康组 （160 mg·kg-1 ） 、辛伐他汀组 （1.3 mg·kg-1 ） 及联合治疗组 （心血康 160 mg·kg-1 +辛伐他汀 1.3 mg·kg-1 ） ，每组 8 只。对照组给予常规饲料喂养， 其余 4 组均给予高脂饲料喂养。同时，各给药组均按照上述剂量灌胃给药，灌胃体积为 10 mL·kg-1 ，每天 1 次， 持续 18 周。给药结束后，检测血清总胆固醇 （TC） 、甘油三酯 （TG） 、低密度脂蛋白胆固醇 （LDL-C） 、高密度脂 蛋白胆固醇 （HDL-C） 水平；采用油红 O 染色法观察小鼠主动脉斑块形成及肝脏脂质聚集情况；ELISA 法检测 血清前蛋白转化酶枯草溶菌素 9 （PCSK9） 水平；qRT-PCR 及 Western Blot 法检测肝脏组织 LDLR、HNF1α、 SREBP2 mRNA 及蛋白表达水平。结果 （1） 与对照组比较，模型组小鼠的血清 TC、TG、LDL-C 水平显著升 高 （P＜0.01） ，HDL-C 水平显著降低 （P＜0.01） ；主动脉根斑块面积百分比、主动脉全体斑块面积百分比、肝 脏脂滴面积百分比均显著升高 （P＜0.01） ；肝脏组织中 LDLR mRNA 及蛋白表达水平显著降低 （P＜0.01） ，血清 PCSK9 水平显著升高 （P＜0.01） ；肝脏组织中 HNF1α、SREBP2 mRNA 及蛋白表达水平均明显升高 （P＜0.05， P＜0.01） 。 （2） 与模型组比较，心血康组及联合治疗组小鼠的血清 TC、TG、LDL-C 水平明显降低 （P＜0.05， P＜0.01） ，HDL-C 水平明显升高 （P＜0.05） ；辛伐他汀组小鼠血清 LDL-C 水平显著降低 （P＜0.01） ；心血康组 及联合治疗组小鼠的主动脉根斑块面积百分比、主动脉全体斑块面积百分比明显降低 （P＜0.05，P＜0.01） ，各 给药组小鼠的肝脏脂滴面积百分比均显著降低 （P＜0.01） ；心血康组及联合治疗组小鼠肝脏组织中 LDLR 蛋白 表达水平明显升高 （P＜0.05） ，血清 PCSK9 水平明显降低 （P＜0.05，P＜0.01） ，肝脏组织中 HNF1α、SREBP2 mRNA 及蛋白表达水平均明显降低 （P＜0.05，P＜0.01） 。 （3） 与辛伐他汀组比较，联合治疗组小鼠血清 HDL-C 水平明显升高 （P＜0.05） ；主动脉根斑块面积百分比、肝脏脂滴面积百分比均明显降低 （P＜0.05，P＜0.01） ；肝脏组织中 LDLR 蛋白表达水平显著升高（P＜0.01），血清 PCSK9 水平显著降低（P＜0.01）；肝脏组织中 HNF1α 蛋白及 SREBP2 mRNA 表达水平均明显降低 （P＜0.05，P＜0.01） 。结论 心血康可能通过抑制 SREBP2 及 HNF1α 表达，调节 PCSK9/LDLR 信号途径，从而发挥对辛伐他汀降脂及抗 AS 作用的协同增效作用。

Objective To investigate the effect and mechanism of Di’ ao Xinxuekang （hereinafter referred to as Xinxuekang） combined with Simvastatin on atherosclerosis（AS） mice. Methods Eight C57BL/6J mice were used as control group，and 32 ApoE-/- mice were randomly divided into model group，Xinxuekang group （160 mg·kg-1 ）， Simvastatin group（1.3 mg·kg-1 ） and combined treatment group（Xinxuekang 160 mg·kg-1 +Simvastatin 1.3 mg·kg-1 ） ， with eight mice in each group. The control group was fed with conventional diet，and the other four groups were fed with high-fat diet. At the same time，each administration group was given intragastric administration according to the above dose， and the volume of intragastric administration was 10 mL·kg-1 ， once a day for 18 weeks. After administration，the levels of serum total cholesterol （TC），triglyceride （TG），low density lipoprotein cholesterol （LDL-C） and high density lipoprotein cholesterol （HDL-C） were detected. Oil red O staining was used to observe the formation of aortic plaque and liver lipid accumulation in mice. Serum PCSK9 level was detected by ELISA. The mRNA and protein expression levels of LDLR，HNF1α and SREBP2 in liver tissues were detected by qRT-PCR and Western Blot. Results（1） Compared with the control group，the levels of serum TC，TG and LDL-C in the model group were significantly increased（P＜0.01） ，and the level of HDL-C was significantly decreased（P＜0.01） . The percentage of aortic root plaque area，the percentage of total aortic plaque area and the percentage of liver lipid droplet area were significantly increased （P＜0.01） . The mRNA and protein expression levels of LDLR in liver tissue were significantly decreased （P＜0.01） ，and the serum PCSK9 level was significantly increased （P＜0.01） . The mRNA and protein expression levels of HNF1α and SREBP2 in liver tissues were significantly increased （P＜ 0.05，P＜0.01） .（2） Compared with the model group，the levels of serum TC，TG and LDL-C in the Xinxuekang group and the combined treatment group were significantly decreased （P＜0.05，P＜0.01） ，and the level of HDL-C was significantly increased（P＜0.05） . The level of serum LDL-C in Simvastatin group was significantly decreased （P＜0.01） . The percentage of aortic root plaque area and the percentage of total aortic plaque area in the Xinxuekang group and the combined treatment group were significantly decreased （P＜0.05，P＜0.01），and the percentage of liver lipid droplet area in each administration group was significantly decreased （P＜0.01） . The protein expression level of LDLR in liver tissue of mice in Xinxuekang group and combined treatment group was significantly increased （P＜0.05） ，the serum PCSK9 level was significantly decreased（P＜0.05，P＜0.01） ，and the mRNA and protein expression levels of HNF1α and SREBP2 in liver tissue were significantly decreased （P＜0.05， P＜0.01）. （3） Compared with the Simvastatin group， the serum HDL-C level in the combined treatment group was significantly increased（P＜0.05） . The percentage of aortic root plaque area and the percentage of liver lipid droplet area were significantly decreased （P＜0.05，P＜0.01） . The protein expression level of LDLR in liver tissue was significantly increased （P＜0.01）， and the serum PCSK9 level was significantly decreased （P＜0.01） . The expression levels of HNF1α protein and SREBP2 mRNA in liver tissues were significantly decreased（P＜0.05，P＜ 0.01） . Conclusion Xinxuekang may play a synergistic effect on lipid-lowering and anti-AS effects of Simvastatin by inhibiting the expressions of SREBP2 and HNF1α and regulating the PCSK9/LDLR signaling pathway.

R285.5

国家自然科学基金青年科学基金项目 （82004175）