曲美他嗪调节中性粒细胞胞外陷阱和单核细胞亚群干预动脉粥样硬化的研究

Effects of trimetazidine on atherosclerosis by modulating neutrophil extracellular traps and monocytes

目的初步分析曲美他嗪(trimetazidine,TMZ)对动脉粥样硬化(AS)的干预作用及潜在机制。方法 ApoE^(-/-)小鼠随机分为模型组、辛伐他汀阳性组(3 mg·kg^(-1)·d^(-1))、TMZ低、高剂量组(10、20 mg·kg^(-1)·d^(-1)),同时设C57BL/6小鼠为对照组。ApoE^(-/-)小鼠高脂饮食喂养8周后,按上述分组灌胃给药,分别通过分光光度法检测血脂水平;小动物超声检测主动脉弓内-中膜厚度(intima-media thickness,IMT);油红O染色分析主动脉斑块面积;流式细胞术观察外周血单核细胞亚群和中性粒细胞胞外陷阱(NETs)标志物表达水平的变化;实时定量PCR检测脾脏IL-1β、IL-18基因表达水平。结果与模型组相比,TMZ高、低剂量组甘油三酯(TG)、总胆固醇(TC)水平均明显降低,IMT明显减小,Ly6C^(hi)单核细胞亚群比例明显降低,NETs表达明显降低,IL-1β、IL-18基因表达水平明显下调,差别有统计学意义(P<0.05)。结论 TMZ能有效延缓AS斑块进展,下调单核细胞亚群比例及NETs的表达,其作用机制可能与调节NETs和单核细胞介导的炎症反应相关。

Aim To observe the effects of trimetazidine on atherosclerosis and potential mechanisms.Methods The ApoE-/-mice were randomly divided into the model group,simvastatin group(3 mg·kg^-1·d^-1),and trimetazidine groups(10,20 mg·kg^-1·d^-1).Meanwhile,C57BL/6 mice were elected as normal control group.After eight weeks of high-fat diet,the ApoE-/-mice were given orally the above drugs.Spectrophotometer was used to detect the levels of serum lipids.Ultrasound was used to detect the inner-media thickness(IMT)of aortic.Oil red O staining was taken to measure the area of plaque in aortic root.Flow cytometry was used to measure the proportion of circulating monocyte subsets and neutrophil extracellular traps(NETs).Real-time quantitative PCR was used to detect the levels of IL-1βand IL-18 gene expression in spleen.Results Compared with model group,the levels of TC and TG in trimetazidine groups decreased significantly,so did the level of IMT.Meanwhile,the proportion of Ly6C hi monocyte subpopulation and NETs also decreased obviously.The gene expressions of IL-1βand IL-18 were reduced significantly.Conclusions Trimetazidine could ameliorate the progression of atherosclerotic plaque,and the mechanism may be related to the regulation of NETs and monocyte-mediated inflammatory reaction.