阿格列汀通过调控神经调节素-1促进糖尿病性心肌病大鼠心肌血管生成和微血管灌注的实验研究  

Experimental study on alogliptin promoting myocardial angiogenesis and microvascular perfusion in diabetic cardiomyopathy rats by regulating neuregulin-1.

作　　者：张朝云 王辉 孙茜 张伟 曹宁 赵红 ZHANG Chao-yun;WANG Hui;SUN Qian(Department of Endocrinology,Hebei Petrochina Central Hospital,Langfang Hebei 065000,China.;Department of Emergency,Hebei Petrochina Central Hospital,Langfang Hebei 065000,China.)

机构地区：[1]河北中石油中心医院内分泌科,河北廊坊065000 [2]河北中石油中心医院急诊科,河北廊坊065000 [3]华北理工大学附属医院心内科,河北唐山063000

出　　处：《临床和实验医学杂志》2022年第19期2020-2025,共6页Journal of Clinical and Experimental Medicine

基　　金：河北省廊坊市科技支撑计划项目(编号:2018013078);河北省医学科学研究课题项目(编号:20201236)。

摘　　要：目的探讨阿格列汀通过调控神经调节素-1促进糖尿病性心肌病大鼠心肌血管生成和微血管灌注的机制。方法实验大鼠分为3组,分别为对照组(n=10)、DCM组(n=10)和阿格列汀治疗组(n=10)。对照组大鼠注射等体积的0.1 mol/L柠檬酸盐缓冲液。DCM组和阿格列汀治疗组通过单次腹膜内注射STZ(55 mg/kg溶于0.1 mol/L柠檬酸盐缓冲液,pH 4.5)诱导糖尿病。DCM组造模成功后,给予0.1 mmol/L柠檬酸盐缓冲液注射。阿格列汀治疗组造模成功后,尾静脉注射阿格列汀,剂量为10μg·kg^(-1)·d^(-1),连续10 d。使用导管MPA心功能分析系统评估心功能,用稳定同位素标记的微球评估心肌血流量,通过CD31免疫组织化学测量毛细血管密度。体外实验中,离体培养人冠状动脉平滑肌细胞(HCASMCs),分为4组,包括对照组、hypo/SD组、阿格列汀处理组(hypo/SD+阿格列汀)和AG1478组(hypo/SD+阿格列汀+AG1478)。使用蛋白质印迹评估蛋白质表达和受体磷酸化。结果与对照组相比,DCM组大鼠的左心室功能、毛细血管密度和心肌血流量(MBF)明显降低,差异均有统计学意义(P<0.05);与DCM组相比,阿格列汀治疗组大鼠的左心室功能和毛细血管密度明显升高,差异均有统计学意义(P<0.05)。与对照组相比,DCM组大鼠的神经调节蛋白-1(NRG-1)的表达水平以及ErbB2、ErbB3的磷酸化水平均升高,血管内皮生长因子(VEGF)表达和Flk1磷酸化、血管生成素-1(Ang-1)、Tie-2磷酸化蛋白表达水平均降低,差异均有统计学意义(P<0.05);与DCM组相比,阿格列汀治疗组大鼠的NRG-1的表达水平以及ErbB2、ErbB3的磷酸化水平均降低,VEGF表达和Flk1磷酸化、Ang-1、Tie-2磷酸化蛋白表达水平均升高,差异均有统计学意义(P<0.05)。在体外,与对照组相比,Hypo/SD组、阿格列汀组HCASMCs中VEGF和Ang-1的表达显著升高,而与阿格列汀组相比,AG1478组HCASMCs中VEGF和Ang-1的表达显著降低,差异均有统计学意义(P<0.05)。�Objective To explore the mechanism of alogliptin in promoting myocardial angiogenesis and microvascular perfusion in diabetic cardiomyopathy rats by regulating neuregulin-1.Methods The experimental rats were divided into 3 groups:control group(n=10),DCM group(n=10)and alogliptin treatment group(n=10).Control group was injected with 0.1 mol/L citrate buffer.DCM group and alogliptin group were treated with a single intraperitoneal injection of STZ(55 mg/kg dissolved in 0.1 mol/L citrate buffer,pH 4.5)to induce diabetes.DCM group was injected with 0.1 mmol/L citrate buffer after modeling.After modeling,alagliptin group was injected into tail vein at a dose of 10μg·kg^(-1)·d^(-1) for 10 consecutive days.Cardiac function was assessed using the ductal MPA cardiac function analysis system.Myocardial blood flow was assessed by stable isotope labeled microspheres.Capillary density was measured by CD31 immunohistochemistry.In vitro experiments,human coronary artery smooth muscle cells(HCASMCs)were cultured in vitro and divided into 4 groups,including control group,HYPO/SD group,alagliptin treatment group(HYPO/SD+alagliptin)and AG1478 group(HYPO/SD+alagliptin+AG1478).Protein expression and receptor phosphorylation were assessed using Western blotting.Results Compared with the control group,left ventricular function,capillary density and myocardial blood flow(MBF)were significantly decreased in the DCM group,the differences were statistically significant(P<0.05);compared with the DCM group,left ventricular function and capillary density were significantly increased in the alogliptin-treated group,the differences were statistically significant(P<0.05).Compared with the control group,the expression level of neuregulin-1(NRG-1)and the levels of ErbB2 and ErbB3 phosphorylation in the DCM group were increased,the expression of vascular endothelial growth factor(VEGF)and Flk1 phosphorylation,Ang-1 and Tie-2 phosphorylated proteins were decreased,and the differences were statistically significant(P<0.05);compared with the DCM gr

关 键 词：大鼠 糖尿病性心肌病 阿格列汀 神经调节素-1 血管生成 微血管灌注 

分 类 号：R587.2[医药卫生—内分泌] R542.2[医药卫生—内科学]