摘要
目的从c-fos信号通路探究美托洛尔减轻急性心肌梗死(AMI)大鼠心肌损伤的作用机制。方法 SPF级SD雄性大鼠150只,其中128只给予结扎左冠状动脉前降支复制AMI动物模型,成功复制90只,死亡38只,将符合AMI模型的90只大鼠随机分为模型组、肝素组及美托洛尔组,每组各30只。另外22只大鼠大仅穿线但不结扎作为假手术组。术后24 h,美托洛尔组大鼠每天同一时间给予0.1%美托洛尔生理盐水10 mg/(kg·d)灌胃,肝素组给予肝素1 250 u/kg皮下注射,其他各组给予等体积生理盐水灌胃,1次/d,共用药4周。术后48 h和4周,分别超声检测大鼠心率(HR)、射血分数(EF)、短轴缩短率(FS)、左心室舒张末期内径(LVIDd)、左心室收缩末期内径(LVIDs)变化。术后4周,Masson法检测心肌梗死面积,TUNEL法检测心肌梗死边缘的凋亡细胞,实时荧光定量聚合酶链反应(q RT-PCR)检测c-fos、ERK1、ERK2 m RNA表达,Western blot检测c-fos、ERK1/2、p-ERK1/2蛋白表达。结果术后48 h和4周,与模型组比较,肝素组和美托洛尔组治疗能使大鼠心率下降(P <0.05)。术后4周,与模型组比较,肝素组和美托洛尔组大鼠心脏EF、FS值均升高(P <0.05),且大鼠心脏LVIDd、LVIDs值降低(P <0.05)。治疗后肝素组和美托洛尔组大鼠心肌梗死面积减小(P<0.05)。术后4周,与模型组比较,肝素组和美托洛尔组蓝色胶原减少,心肌纤维化水平降低。TUNEL结果显示,治疗后肝素组和美托洛尔组大鼠心肌梗死周边细胞的凋亡率降低(P<0.05)。qRT-PCR结果显示,治疗后肝素组和美托洛尔组大鼠心肌细胞c-fos、ERK1、ERK2的mRNA表达低于模型组(P<0.05)。Western blot结果显示,ERK1/2蛋白表达各组间比较差异无统计学意义(P>0.05),治疗后肝素组和美托洛尔组大鼠心肌细胞c-fos、p-ERK1/2蛋白表达低于模型组(P <0.05)。结论美托洛尔能明显减轻大鼠AMI后心肌损伤程度,其作用机制可能与p-ERK1/2-c-fos途径受到抑制有关。
Objective To explore the mechanism of Metoprolol on myocardial injury in acute myocardial infarction(AMI)rats through c-fos signaling pathway.Methods Of 150 SPF class male SD rats,128 rats were given ligation of the anterior descending branch of the left coronary artery to establish AMI animal models,and 22 rats were threaded but not ligated as the sham-operation group.The 90 rats consistent with the AMI model were randomly divided into three groups:a model group,a heparin group and a Metoprolol group,with 30 in each group.After 24 h,the rats in the Metoprolol group were given 0.1%Metoprolol normal saline 10 mg/(kg?d)through gastric lavage at the same time every day,the rats in the heparin group received subcutaneous injection of heparin(1,250 U/kg),and the rats in the remaining group were given equal volume of normal saline for intragastric administration,once a day,all for 4 weeks.At the 48th h and the 4th week after operation,the changes of heart rate(HR),ejection fraction(EF),fraction shortening(FS),left ventricular end-diastolic diameter(LVEDD)and left ventricular endsystolic diameter(LVESD)in the rats were measured by ultrasonography.At the 4th postoperative week,the area of myocardial infarction was measured using Masson method.Apoptotic cells at the edge of myocardial infarction was tested by TUNEL method.qRT-PCR was used to detect the expression levels of c-fos,ERK1 and ERK2 mRNAs.And the protein expression levels of c-Fos,ERK1/2 and p-ERK1/2 were detected using Western blot.Results Compared with the model group,heparin and Metoprolol reduced heart rate significantly at the 48th h and the 4th week after AMI(P<0.05).In the 4th week after surgery,compared with the model group,the EF and FS values increased(P<0.05),while LVEDD and LVESD reduced in the heparin group and the Metoprolol group(P<0.05).The area of myocardial infarction decreased significantly after treatment with heparin or Metoprolol(P<0.05).After 4 weeks,compared with the model group,blue collagen decreased and myocardial fibrosis level also decreased in the heparin and Metoprolol groups.TUNEL results showed the apoptosis rate of the myocardial cells around the infarction areas of the rats decreased significantly after heparin or Metoprolol treatment(P<0.05).The results of qRT-PCR showed c-fos,ERK1 and ERK2 mRNA expression levels in the cardiac myocytes of the rats after heparin or Metoprolol treatment were significantly lower than those in the model group(P<0.05).Western blot showed that ERK1/2 protein expression level had no significant difference among the groups(P>0.05);however,c-fos and p-ERK1/2 protein expression levels in the rat cardiomyocytes of the heparin and Metoprolol groups were significantly lower than those in the model group(P<0.05).Conclusions Metoprolol can obviously alleviate myocardial damage after AMI in rats,and the mechanism may be related to the inhibition of p-ERK1/2-c-fos pathway.
作者
徐燕
Yan Xu(Department of Cardiology,Beijing Royal Integrative Medicine Hospital,Beijing 100049,China)
出处
《中国现代医学杂志》
CAS
2018年第31期7-13,共7页
China Journal of Modern Medicine
