文章摘要
程晓洪,李家富.GLP-1R激动剂对阿霉素诱导大鼠心肌纤维化的作用*[J].安徽医药,待发表.
GLP-1R激动剂对阿霉素诱导大鼠心肌纤维化的作用*
投稿时间:2021-11-25  录用日期:2021-12-21
DOI:
中文关键词: 心肌纤维化  心室重构  胰高血糖素样肽受体  cGMP-PKG信号通路
英文关键词: 
基金项目:四川省2011项目-四川省心血管疾病防治协同创新中心(xtcx2019-14)。
作者单位地址
程晓洪 西南医科大学附属医院心血管内科 西南医科大学附属医院外科大楼收发室
李家富 西南医科大学附属医院 
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中文摘要:
      目的:研究GLP-1R激动剂对阿霉素诱导的心肌纤维化大鼠的影响及机制。方法:将40只SD大鼠随机数字表法分为正常组(N组)、阿霉素组(DOX组)、阿霉素+度拉糖肽组(GLP-1RA组)、阿霉素+度拉糖肽+Exendin(9-39)组(EX9-39组)。除N组外,利用阿霉素(3mg/kg tiw)建立心肌纤维化大鼠模型,GLP-1RA组予以度拉糖肽1mg/kg/w 皮下注射,EX-9-39组予以度拉糖肽 1mg/kg/w 皮下注射及Ex9-39 200ug/kg/d腹腔注射。4周后完善心脏超声测量左室收缩末期内径(LVDs),左室舒张末期内径(LVDd)、左室短轴缩短率(FS)和左室射血分数(LVEF)后处死大鼠,HE染色观察心脏组织形态学变化;Masson染色检测胶原含量;Western blot测胰高血糖素样肽-1受体(GLP-1R)、肌浆网钙泵(SERCA2a)、受磷蛋白(PLB)、磷酸化受磷蛋白(p-PLB)、蛋白激酶G(PKG)、钙调蛋白激酶II(CaMKII)、磷酸化兰尼碱受体(p-RyR);Elisa测N端脑钠肽前体(NT-proBNP)、环单磷酸鸟苷(cGMP)、胰高血糖素样肽-1(GLP-1)、血糖(GLU)、胰岛素(INS)。结果:(1)各组间血糖及胰岛素的浓度均无显著性差异(P>0.05);(2)与DOX组相比,GLP-1RA组纤维化程度减轻(P<0.05),GLP-1R、PKG、SERCA2a、p-PLB、cGMP、GLP-1、LVEF、FS水平升高(P<0.05),CVF、PLB、p-RYR、CaMKII、NT-proBNP 、LVDs、LVDd水平降低(P<0.05);与GLP-1RA组相比,Ex9-39组GLP-1RA组纤维化程度增加(P<0.05),GLP-1R、PKG、SERCA2a、p-PLB、cGMP、GLP-1、LVEF、FS水平降低(P<0.05),CVF、PLB、p-RYR、CaMKII、NT-proBNP 、LVDs、LVDd水平降升高(P<0.05)。结论:(1)GLP-1RA可改善阿霉素诱导的心肌纤维化而逆转心肌重构;(2)GLP-1RA逆转心肌重构可能与cGMP-PKG通路相关。
英文摘要:
      Objective: to study the effect and mechanism of GLP- 1R agonist on doxorubicin -induced myocardial fibrosis in rats. Methods: 40 SD rats were randomly divided into normal group (N group), doxorubicin group (DOX group), doxorubicin + dulapeptide group (GLP- 1RA group), doxorubicin + dulapeptide + Exendin (9-39) group (EX9- 39 group). Except N group, the rat model of myocardial fibrosis was established by doxorubicin (3mg/kg tiw). The rats in GLP- 1RA group were subcutaneously injected with dulapeptide 1mg/kg/w, and the rats in EX9-39 group were subcutaneously injected with dulapeptide 1mg/kg/w and Ex9- 39 200ug/kg/d. Four weeks later, the rats were sacrificed after ultrasonic measurement of LVDd, LVDs, LVEF and FS. The morphological changes of heart tissue were observed by HE staining, collagen content was detected by Masson staining, GLP-1R, SERCA2a, PLB, p-PLB, PKG, CaMKII, p-RyR were measured by Western blot. NT-proBNP, cGMP, GLP-1, blood glucose and insulin were measured by Elisa. Results: (1) there was no significant difference in the concentration of blood glucose and insulin among the four groups(P>0.05). (2) compared with DOX group, the degree of fibrosis in GLP- 1RA group decreased(P<0.05),the levels of GLP-1R, PKG, SERCA2a, p-PLB, cGMP, GLP-1, LVEF and FS increased(P<0.05), while the levels of CVF, PLB, p-RYR, CaMKII, NT-proBNP, LVDs and LVDd decreased(P<0.05).EX9-39 antagonized part of the effect of GLP-1RA. Conclusion: (1) GLP-1RA can improve myocardial fibrosis induced by doxorubicin and reverse myocardial remodeling.(2) the reversal of myocardial remodeling by GLP-1RA maybe related to cGMP- PKG signal pathway.
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