局部应用辛伐他汀和机械预处理方法预防静脉移植物再狭窄的研究  

Study of preventing venous graft restenosis by local application of simvastatin and mechanical preconditioning

作　　者：赵晨宇 潘予韦 贾六军[3] 张岩[1] 段亚冰 丁力 孙寒松[1] ZHAO Chenyu;PAN Yuwei;JIA Liujun;ZHANG Yan;DUAN Yabing;DING Li;SUN Hansong(Department of Cardiac Surgery,Fuwai Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,100039,P.R.China;Department of Biochemistry and Molecular Biology,College of Biology,China Agricultural University,Beijing,100094,P.R.China;Animal Laboratory Center,Fuwai Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,102300,P.R.China)

机构地区：[1]中国医学科学院北京协和医学院阜外医院成人心外科,北京100039 [2]中国农业大学生物学院生物化学与分子生物学系,北京100094 [3]中国医学科学院北京协和医学院阜外医院动物实验中心,北京102300

出　　处：《中国胸心血管外科临床杂志》2023年第2期291-298,共8页Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

基　　金：北京市自然科学基金面上项目(7212082);北京协和医学院2019年研究生创新基金项目(2019-1002-49)。

摘　　要：目的探究局部应用辛伐他汀和机械预处理方法对静脉移植物内膜增生的影响及机制。方法在体实验选用新西兰兔12只,随机分为4组:空白对照组、辛伐他汀局部处理组、机械预处理组、药物机械联合预处理组,每组3只。超声评价移植物管壁改变和移植物内血流速度,病理切片评价血管内膜增生情况。体外实验培养人脐血管内皮细胞,设辛伐他汀组和溶剂对照组,检测YAP磷酸化、下游靶基因表达量和细胞增殖情况。结果血管超声显示除辛伐他汀局部处理组外,其它3组术后21 d静脉移植物内流速均较术后7 d明显升高(P<0.01)。病理切片显示辛伐他汀局部处理组、机械预处理组、药物机械联合预处理组、空白对照组的新生内膜厚度分别为:(45.56±4.11)μm、(201.28±16.71)μm、(143.57±7.82)μm、(249.45±13.33)μm,与空白对照组相比差异均有统计学意义(P<0.05)。体外实验结果显示,与溶剂对照组相比,高浓度辛伐他汀(5 mmol/L)组细胞死亡,低浓度辛伐他汀(2.5 mmol/L)组细胞增殖受抑制(P<0.05),辛伐他汀组YAP蛋白表达量不变,磷酸化YAP蛋白表达量明显增加(P<0.05),下游靶基因ccn1表达下调(P<0.001)。结论血管内局部应用辛伐他汀和机械预处理方法单用或联用均能抑制静脉移植物内膜增生;高浓度的辛伐他汀有细胞毒性,低浓度的辛伐他汀有抑制细胞增殖的作用;辛伐他汀通过抑制YAP入核、降低细胞增殖相关靶基因ccn1的转录发挥抑制新生内膜形成的作用。Objective To investigate the effect of simvastatin and mechanical pretreatment on intimal hyperplasia of venous graft and its mechanism.Methods Twelve New Zealand rabbits were selected and randomly divided into 4 groups:a blank control group,a simvastatin topical treatment group,a mechanical precondition group and a combined group(n=3 in each group).Ultrasound was used to evaluate the changes of graft wall and blood flow velocity in the graft,and pathological section was used to evaluate the intimal hyperplasia.Human umbilical cord endodermal cells were cultured in vitro.A simvastatin group and a solvent control group were set to detect YAP phosphorylation,downstream target gene expression and cell proliferation.Results Vascular ultrasound showed that except the simvastatin topical treatment group,the flow velocity in vein grafts in the other three groups significantly increased 21days after surgery compared with 7 days after surgery(P<0.01).Pathological sections showed that the thickness of new intima in the simvastatin topical treatment group,mechanical precondition group,combined group and blank control group were 45.56±4.11μm,201.28±16.71μm,143.57±7.82μm,249.45±13.33μm,respectively,and there were statistical differences compared with the blank control group(P<0.05).In vitro results showed that compared with the solvent control group,cell death was observed in high concentration simvastatin(5 mmol/L)group,cell proliferation was inhibited in low concentration simvastatin(2.5 mmol/L)group(P<0.05),the expression of YAP protein in the simvastatin group was unchanged,but the expression of phosphorylated YAP protein significantly increased(P<0.05),and the expression of downstream target gene ccn1 was down-regulated(P<0.001).Conclusion Intravascular local application of simvastatin and mechanical preconditioning alone or in combination can inhibit intimal hyperplasia of venous graft.High concentration of simvastatin has cytotoxicity,while low concentration of simvastatin has inhibitory effect on cell prolifer

关 键 词：局部用药 辛伐他汀 机械预处理 静脉移植物再狭窄 冠状动脉旁路移植术 

分 类 号：R654.2[医药卫生—外科学]