口服雷帕霉素抑制哺乳动物雷帕霉素靶蛋白(mTOR)防治支架内再狭窄的实验研究

摘要

目的 联合应用血管内超声(IVUS)、病理学及免疫组织化学技术,探讨口服雷帕霉素抑制支架内再狭窄的作用及其分子机制.方法 通过球囊损伤腹主动脉和高脂(1％胆固醇)饲料喂养雄性新西兰纯种兔8周,然后将其分为裸支架组(BMS)、裸支架+口服雷帕霉素组(BMS+ RAPA)和雷帕霉素药物涂层支架组( DES),每组8只.继续高胆固醇饲料喂养4周后,应用IVUS检测各组实验兔支架置人前后腹主动脉病变部位管腔最小直径(MLD)、血管外弹力膜面积(EEMA)、管腔面积(LA)、斑块面积(PA)及斑块负荷(PB),并计算管腔丢失量.病理学观察支架内增生组织的病理学形态改变,免疫组织化学检测哺乳动物雷帕霉素靶蛋白(mTOR)在局部斑块中的表达情况.结果 IVUS结果显示BMS+RAPA组及DES组的PA、PB均明显小于BMS组(P均＜0.01),而MLD明显高于BMS组,支架植入4周后管腔丢失明显小于BMS组(P均＜0.05)；病理学检测显示BMS组支架植入后内膜增生明显,管腔面积狭窄率明显大于BMS+RAPA组及DES组.BMS+RAPA组及DES组的斑块局部mTOR表达明显低于BMS组.结论 口服雷帕霉素通过抑制mTOR抑制斑块生长,降低支架内再狭窄；口服雷帕霉素配合裸支架与雷帕霉素药物支架抑制支架内再狭窄的作用相似.%Objective To identify the mechanisms of oral administered rapamycin on the prevention of restenosis after stent implantation with intravascular ultrasound (IVUS) and pathology.Methods Twenty-four New Zealand white rabbits underwent balloon-induced abdominal aortic wall injury and were given a diet of 1 ％ cholesterol for 8 weeks.Then,the rabbits were divided into three groups:the bare metal stent group(BMS group),the bare metal stent with oral rapamycin group(BMS + RAPA group) and the rapamycin eluting stent group(DES group).Rabbits in the RAPA and BMS + RAPA groups received a daily oral dose of rapamycin(0.5 mg/kg),whereas rabbits in the DES group received no drugs.All the rabbits were euthanized after the 4-week intervention.Serum lipids were measured.IVUS and pathologic studies were performed.The minimal luminal diameter (MLD),external elastic membrane (EEM) area,lumen area (LA),and plaque area(PA),plaque burden(PB) were measured.Mammalian target of rapamycin(mTOR) expression level was examined by immunohistochemistry.Results After the 4-week intervention,there was no significant difference of serum lipid levels among the three groups.IVUS showed that oral administration of rapamycin in the BMS + RAPA groups showed similar effects in reducing PA and PB as the DES group,which all were better than the BMS group.The BMS + RAPA and DES groups showed much more MLD and less lumen reduction,compared with the BMS group( P ＜0.05).Level of mTOR expression of the BMS + RAPA group and DES group was significantly lower than that of BMS group.Conclusions Oral administration of rapamycin demonstrates the same effect in the reduction of plaque burden and stent restenosis as the rapamycin eluting stent.Inhibition of mTOR by rapamycin involves in the stent restenosis.