度拉糖肽皮下注射对糖尿病小鼠心肌纤维化的改善作用及其机制  

Effect of subcutaneous injection of Dulaglutide on myocardial fibrosis of diabetic mice and its mechanism

作　　者：蓝杉杉 莫薇薇[2] 韦柳凤 杨海燕[1] 李励[1] 冼晶[1] 卢德成[1] 秦映芬[1] 梁杏欢[1] 罗佐杰[1] LAN Shanshan;MO Weiwei;WEI Liufeng;YANG Haiyan;LI Li;XIAN Jing;LU Decheng;QIN Yingfen;LIANG Xinghuan;LUO Zuojie(Department of Endocrinology,The First Affiliated Hospital of Guangxi Medical University,Nanning 530021,China)

机构地区：[1]广西医科大学第一附属医院内分泌科,南宁530021 [2]广西医科大学第四附属医院肾内科

出　　处：《山东医药》2023年第14期45-49,共5页Shandong Medical Journal

摘　　要：目的探讨度拉糖肽皮下注射对糖尿病小鼠心肌纤维化的改善作用及其机制。方法将28只Balb/c小鼠分为正常对照组、糖尿病组(DM组)、度拉糖肽低剂量组(LD组)和度拉糖肽高剂量组(HD组),每组各7只。正常对照组正常喂养,DM、LD、HD组以高脂饮食联合STZ注射建立糖尿病模型,随后LD组、HD组分别给予600、1000μg/kg度拉糖肽皮下注射,正常对照组和DM组给予等量生理盐水皮下注射,1次/周,连续6周。处死小鼠,取心肌组织,采用HE染色观察心肌组织形态学改变,Masson染色检测心肌纤维化面积,RT-PCR法检测心肌组织核苷酸结合寡聚化结构域样受体蛋白3(NLRP3)、白细胞介素1β(IL-1β)、转化生长因子β_(1)(TGF-β_(1))mRNA表达,Western blotting法检测心肌组织胰高血糖素样肽1受体(GLP-1R)蛋白及IL-1β、TGF-β_(1)、Ⅰ型胶原蛋白(CollagenⅠ)、NLRP3蛋白表达。结果与正常对照组比较,DM组心肌细胞排列紊乱,心肌细胞肥大,胞质染色不均,局部淋巴细胞浸润明显,血管扩张;与模型组比较,LD组、HD组心肌组织病理改变均有改善,且HD组改善程度更明显。与正常对照组比较,DM组心肌纤维化面积增加;与DM组比较,LD组、HD组心肌纤维化面积减少,且HD组少于LD组(P均<0.05)。与正常对照组比较,DM组NLRP3、IL-1β、TGF-β_(1)、CollagenⅠmRNA表达水平增加;与DM组对比,HD组IL-1β、TGF-β_(1)、CollagenⅠmRNA表达水平降低,且HD组TGF-β_(1) mRNA表达水平低于LD组(P均<0.05)。与正常对照组比较,DM组GLP-1R蛋白表达减少;与DM组比较,LD组、HD组GLP-1R蛋白表达增加(P均<0.05),LD组与HD组无统计学差异(P>0.05)。与正常对照组比较,DM组NLRP3、cleaved Caspase-1、IL-1β、TGF-β_(1)、CollagenⅠ蛋白表达均升高(P均<0.05);与DM组比较,LD组TGF-β_(1)蛋白表达下降,HD组NLRP3、IL-1β、TGF-β_(1)、CollagenⅠ蛋白表达下降(P均<0.05),LD组与HD组各蛋白表达比较均无统计学差异(P均>0.05)。结论度Objective To observe the effect of subcutaneous injection of Dulaglutide on myocardial fibrosis in diabe⁃tes mellitus(DM)mice and to explore its potential mechanism.Methods Twenty-eight Balb/c mice were divided into the normal control group,DM group,low-dose Dulaglutide(LD)group and high-dose Dulaglutide(HD)group,with 7 mice in each group.Mice in the normal control group were fed normally,mice in the DM group,LD group and HD group were fed high-fat diet combined with STZ injection to construct DM models;subsequently,the mice in the LD group and HD group were subcutaneously injected with 600 and 1000μg/kg Dulaglutide,respectively;mice in the normal control group and DM group were subcutaneously injected with equal volume of normal saline,once a week,for 6 consecutive weeks.The mice were killed to obtain the myocardial tissues.The histological changes of myocardial tissues were observed by HE staining,the myocardial fibrosis area of mice in each group was detected by Masson staining,and mRNA levels of NOD-like receptor family pyrin domin-containing 3(NLRP3),IL-1βand transforming growth factor-β_(1)(TGF-β_(1))were de⁃tected by RT-PCR;the protein expression levels of GLP-1R,IL-1β,TGF-β_(1),CollagenⅠand NLRP3 were detected by Western blotting.Results Compared with the control group,the DM group showed disordered myocardial cell arrange⁃ment,myocardial cell hypertrophy,uneven cytoplasmic staining,obvious local lymphocyte infiltration and vascular dila⁃tion.Compared with the DM group,the pathological changes of myocardial tissues in the LD and HD groups were signifi⁃cantly improved,and the pathological changes of myocardial tissues in HD group were further improved compared with the LD group.Compared with the normal control group,the myocardial fibrosis area in the DM group significantly increased(P<0.05).Compared with DM group,the area of myocardial fibrosis in LD and HD groups significantly decreased,and that in the HD group was small than the LD group(all P<0.05).Compared with the normal control gro

关 键 词：心肌纤维化 胰高血糖素样肽1受体 度拉糖肽 NLRP3/IL-1β/TGF-β_(1)信号通路 糖尿病心肌病 

分 类 号：R587.2[医药卫生—内分泌]