An Ac-SDKP analogue resistant to angiotensin converting enzyme exhibits anti-fibrosis effects and improves heart function in mice after myocardial infarction  

抗纤维化Ac-SDKP异构体:改善小鼠心肌梗死后心室重构（英文）

作　　者：陈建辉[1,2] 马晓雯[3] 张昭[3] 张英启[3] 苑媛[2] 李萌[3] 

机构地区：[1]河南省焦作市中国人民解放军第91中心医院,河南焦作454003 [2]第四军医大学西京医院心血管内科,陕西西安710032 [3]第四军医大学药学系生物技术中心,陕西西安710032

出　　处：《Journal of Chinese Pharmaceutical Sciences》2015年第12期789-800,共12页中国药学（英文版）

基　　金：National Science and Technology Major Projects(Invention and Creation of New Drugs)of China 2011ZXJ09104-01B;Xijing project 9XJZT13M17

摘　　要：To explore the effect of an Ac-SDKP analog on left ventricular remodeling after myocardial infarction,we synthesized the analog Ac-SD_DK_DP by replacing Asp and Lys with their D isomers.The biological activities of Ac-SD_DK_DP were confirmed using flow cytometry,qRT-PCR,Western blots and fluorescence microscopy.The protective effects of Ac-SD_DK_DP on infarcted hearts were assessed in mice with myocardial infarction（MI）.The half-life of Ac-SD_DK_DP was prolonged to over 2 h from a few minutes that Ac-SDKP has.Compared with Ac-SDKP,the analog exhibited stronger inhibition on the differentiation of macrophages,expression of arginase I（ARG I） and TGF-β1 in mature macrophages,proliferation and secretion of collagen type I in cardiac fibroblasts.In MI mice mode,Ac-SD_DK_DP decreased collagen deposition and TGF-β1 expression in myocardium,thus improving the FS（%） to 23.0±7.8 compared with 11.2±6.2 in untreated mice and 11.7±5.3 in Ac-SDKP treated mice（P0.05）.This work shows that the Ac-SDKP analogue is potentially useful for protective treatment for heart failure post-MI.In addition,the anti-fibrosis mechanism of Ac-SDKP was correlated with the alternative activation（M2） of macrophages by assessing ARG I and TGF-β1,two important fibrosis-related molecules secreted in M2 macrophages.本文主要目的是研究体外合成的Ac-SDKP异构体抗血管紧张素转化酶(ACE)降解的特性及其对心梗后心室重构的影响。我们通过D型氨基酸替代Asp和Lys的方式制备了一个Ac-SDKP小肽的异构体Ac-SDDKDP(中国发明专利ZL201110436671.9),并通过建立心肌梗死小鼠动物模型,培养心肌成纤维细胞,结合流式细胞仪,qRT-PCR,Western Blots等技术评估Ac-SDDKDP对梗死心肌的保护作用。结果发现,Ac-SDDKDP使Ac-SDKP的半衰期从数分钟延长至2小时。AcSDDKDP主要通过抑制梗死心肌中巨噬细胞的旁路激活(Alternative activation,M2),减少TGF-β1、ARG I、胶原蛋白I等一系列分子的分泌来发挥抗纤维化的功能。与对照组小鼠左室短轴缩短率(FS)11.2±6.2相比,Ac-SDDKDP组FS为23.0±7.8,Ac-SDKP组FS为11.7±5.3(P<0.05)。结论:该研究证实Ac-SDKP异构体Ac-SDDKDP通过抑制梗死心肌中巨噬细胞的旁路激活(M2),减少TGF-β1、ARGI分泌发挥治疗缺血性心脏病的药用潜能。

关 键 词：Ac-SDKP ANALOGUE ANTI-FIBROSIS Myocardial infarction Heart failure 

分 类 号：R542.22[医药卫生—心血管疾病]