抗纤维化Ac-SDKP异构体: 改善小鼠心肌梗死后心室重构

doi:10.5246/jcps.2015.12.101

中国药学(英文版) ›› 2015, Vol. 24 ›› Issue (12): 789-800.DOI: 10.5246/jcps.2015.12.101

抗纤维化Ac-SDKP异构体: 改善小鼠心肌梗死后心室重构

陈建辉^1,2, 马晓雯³, 张昭³, 张英启³, 苑媛^2*, 李萌^3*

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

收稿日期:2015-06-16 修回日期:2015-07-30 出版日期:2015-12-22 发布日期:2015-08-15
通讯作者: Tel.: 86-29-84773488/86-29-84775183, Fax: 86-29-83247213/86-29-84771177, E-mail: lemon781106@yahoo.com.cn, yuanfmmu@163.com
基金资助:
National Science and Technology Major Projects (Invention and Creation of New Drugs) of China 2011ZXJ09104-01B and Xijing project 9XJZT13M17.

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

Jianhui Chen^1,2, Xiaowen Ma³, Zhao Zhang³, Yingqi Zhang³, Yuan Yuan^2*, Meng Li^3*

1. The Ninety-first Central Hospital of the Chinese people’s liberation army, Jiaozuo 454003, China
2. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China
3. Biotechnology Center, School of Pharmacy, Fourth Military Medical University, Xi'an 710032, China

Received:2015-06-16 Revised:2015-07-30 Online:2015-12-22 Published:2015-08-15
Contact: Tel.: 86-29-84773488/86-29-84775183, Fax: 86-29-83247213/86-29-84771177, E-mail: lemon781106@yahoo.com.cn, yuanfmmu@163.com
Supported by:
National Science and Technology Major Projects (Invention and Creation of New Drugs) of China 2011ZXJ09104-01B and Xijing project 9XJZT13M17.

摘要/Abstract

摘要：

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-SD_DK_DP(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-SD_DK_DP对梗死心肌的保护作用。结果发现, Ac-SD_DK_DP使Ac-SDKP的半衰期从数分钟延长至2小时。Ac-SD_DK_DP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-SD_DK_DP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-SD_DK_DP通过抑制梗死心肌中巨噬细胞的旁路激活(M2), 减少TGF-β1、ARG I分泌发挥治疗缺血性心脏病的药用潜能。

关键词: 抗纤维化, 心肌梗死, 心衰, 异构体, 心室重构

Abstract:

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 improvingthe 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 (P<0.05). 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.

Key words: Ac-SDKP, Analogue, Anti-fibrosis, Myocardial infarction, Heart failure

中图分类号:

R965

Supporting:

陈建辉, 马晓雯, 张昭, 张英启, 苑媛, 李萌. 抗纤维化Ac-SDKP异构体: 改善小鼠心肌梗死后心室重构[J]. 中国药学(英文版), 2015, 24(12): 789-800.

Jianhui Chen, Xiaowen Ma, Zhao Zhang, Yingqi Zhang, Yuan Yuan, Meng Li. An Ac-SDKP analogue resistant to angiotensin converting enzyme exhibits anti-fibrosis effects and improves heart function in mice after myocardial infarction[J]. Journal of Chinese Pharmaceutical Sciences, 2015, 24(12): 789-800.

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抗纤维化Ac-SDKP异构体: 改善小鼠心肌梗死后心室重构

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

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