ZLY18通过抑制TGF-β1/Smads通路改善血管紧张素Ⅱ诱导的心肌纤维化  

ZLY18 protects against angiotensinⅡ-induced cardiac fibrosis via inhibiting TGF-β1/Smads pathway

作　　者：马定虎 周宗涛 李政 张淯涬 路静 刘培庆 MA Ding-hu;ZHOU Zong-tao;LI Zheng;ZHANG Yu-xing;LU Jing;LIU Pei-qing(School of Pharmacy,Jinan University,Guangzhou 510632,China;School of Pharmacy,Guangdong Pharmaceutical University,Guangzhou 510008,China;School of Pharmacy,Sun Yat-Sun University,Guangzhou 510275,China)

机构地区：[1]暨南大学药学院,广东广州510632 [2]广东药科大学药学院,广东广州510008 [3]中山大学药学院,广东广州510275

出　　处：《中国药理学通报》2023年第2期229-238,共10页Chinese Pharmacological Bulletin

基　　金：国家自然科学基金联合基金重点项目(No U21A20419);广州市基础与应用基础研究项目(No 202102020173);广西心脑血管疾病防治精准医学重点实验室开放课题(No GXXNXG202101)。

摘　　要：目的探究化合物ZLY18对血管紧张素Ⅱ(angiotensinⅡ,AngⅡ)诱导的心肌纤维化的作用及机制。方法采用Ang II在细胞水平和动物水平上建立心肌纤维化模型。体外实验:将心肌成纤维细胞分为对照组、模型组、ZLY18(L)组、ZLY18(M)组和ZLY18(H)组,分别给予ZLY181、2、5μmol·L^(-1);体内实验:将小鼠随机分为对照组、模型组、ZLY18(L)组、ZLY18(M)组和ZLY18(H)组,分别给予ZLY1810、20和50 mg·kg^(-1),模型组和药物组同时给予AngⅡ诱导心肌纤维化模型。通过免疫印迹和免疫荧光检测蛋白水平的变化;通过超声心动检测小鼠心功能指标;通过HE染色等方法观察心肌细胞形态、细胞排列和胶原纤维沉积等。结果体内、外成功建立了AngⅡ诱导的心肌纤维化模型,给予ZLY18处理后均能改善由AngⅡ引起的纤维化相关蛋白升高,小鼠心功能异常等。此外,ZLY18能够抑制由AngⅡ引起的TGF-β1、Smad3的磷酸化水平升高,Smad2/3入核增加,提示ZLY18抗纤维化作用可能与TGF-β1/Smads信号通路激活有关。结论ZLY18对AngⅡ诱导的心肌纤维化具有一定的保护作用,该作用可能是通过抑制TGF-β1/Smads信号通路异常激活。Aim To explore the effect of ZLY18 on angiotensinⅡ-induced cardiac fibrosis and the underlying mechanism.Methods AngⅡwas used to induce cardiac fibrosis in vitro and in vivo.Cardiac fibroblasts were divided into blank control group,model group and medicine group.The medicine group was subdivided into ZLY18(L)group,ZLY18(M)group and ZLY18(H)group.Compound ZLY18 was given 1,2,5μmol·L^(-1) respectively.C57BL/6 mice were randomly divided into control group,model group and medicine group.The medicine group were subdivided into ZLY18(L)group,ZLY18(M)group and ZLY18(H)group.Compound ZLY18 was given 10,20 and 50 mg·kg^(-1) respectively.Both the model group and the medicine group were given with AngⅡto induce cardiac fibrosis.The changes of protein levels were detected by Western blot and immunofluorescence.The changes of cardiac function indexes in C57BL/6 mice were detected by small animal echocardiography.The morphology,cell arrangement and collagen fibers of cardiac fibroblasts were observed by tissue section staining and other methods.Results The model of AngⅡ-induced myocardial fibrosis was successfully established at the cell and animal levels,and ZLY18 treatment improved the elevated fibrosis-related protein caused by AngⅡand abnormal cardiac function in mice.Moreover,ZLY18 was able to inhibit the increased phosphorylation of TGF-1 and Smad3 caused by AngⅡand increased Smad2/3 nuclear entry,suggesting that the antifibrotic effect of ZLY18 might be related to the activation of TGF-1/Smads signaling pathway.Conclusions ZLY18 has a protective effect on AngⅡ-induced cardiac fibrosis.ZLY18 may inhibit TGF-β/Smads signaling pathway activation to exert anti-fibrotic effects.

关 键 词：ZLY18 血管紧张素Ⅱ 心肌纤维化 心功能 TGF-β1/Smads 入核 

分 类 号：R-332[医药卫生] R322.11R331.31R542.23R916.4