Dexrazoxane Protects Cardiomyocyte from Doxorubicin-Induced Apoptosis by Modulating miR-17-5p
Dexrazoxane Protects Cardiomyocyte from Doxorubicin-Induced Apoptosis by Modulating miR-17-5p
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右雷佐生通过调节 miR-17-5p 保护心肌细胞免受阿霉素诱导的细胞凋亡
DOI：
10.1155/2020/5107193
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发表时间：
2020
影响因子：
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通讯作者：
Li Jian
中科院分区：
文献类型：
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作者：
Yu Xiaoxue;Ruan Yang;Shen Tao;Qiu Quan;Yan Mingjing;Sun Shenghui;Dou Lin;Huang Xiuqing;Wang Que;Zhang Xiyue;Man Yong;Tang Weiqing;Jin Zening;Li Jian
在临床实践中，多柔比星的使用受到其危及生命的心脏毒性的阻碍。右雷佐生是FDA批准的唯一一种用于预防多柔比星诱导的心脏毒性的心脏保护药物。然而，右雷佐生的机制尚未完全了解。本研究旨在探讨右雷佐生抗阿霉素心脏毒性的可能分子机制。我们建立了阿霉素诱导的小鼠心肌细胞损伤模型。将雄性C57 BL/6 J小鼠随机分配到对照组（Con）、多柔比星处理组（DOX）、多柔比星加右雷佐生处理组（DOX+DEX）和右雷佐生处理组（DEX）中。超声心动图和组织学分析，以评估心脏功能和结构。在体外对用/不用DEX处理的DOX处理的心肌细胞进行DNA梯状化、qRT-PCR和蛋白质印迹。然后用miR-17- 5 p模拟物或抑制剂转染心肌细胞以分析其下游靶标。我们的研究结果表明，右雷佐生在体内和体外通过减少心肌细胞凋亡来预防多柔比星诱导的心脏损伤。microRNA在心血管疾病中起着重要作用。我们的数据显示，右雷佐生可以上调miR-17- 5 p的表达，miR-17- 5 p通过调节细胞凋亡在缺氧反应中发挥细胞保护作用。此外，miRNA和蛋白质分析显示miR-17- 5 p显著减弱暴露于阿霉素的心肌细胞中磷酸酶和张力蛋白同源物（PTEN）的表达。总而言之，右雷佐生可能通过调节miR-17- 5 p/PTEN级联反应的表达，对阿霉素诱导的心肌细胞凋亡发挥心脏保护作用。
The usage of doxorubicin is hampered by its life-threatening cardiotoxicity in clinical practice. Dexrazoxane is the only cardioprotective medicine approved by the FDA for preventing doxorubicin-induced cardiac toxicity. Nevertheless, the mechanism of dexrazoxane is incompletely understood. The aim of our study is to investigate the possible molecular mechanism of dexrazoxane against doxorubicin-induced cardiotoxicity. We established a doxorubicin-induced mouse and cardiomyocyte injury model. Male C57BL/6J mice were randomly distributed into a control group (Con), a doxorubicin treatment group (DOX), a doxorubicin plus dexrazoxane treatment group (DOX+DEX), and a dexrazoxane treatment group (DEX). Echocardiography and histology analyses were performed to evaluate heart function and structure. DNA laddering, qRT-PCR, and Western blot were performed on DOX-treated cardiomyocytes with/without DEX treatment in vitro. Cardiomyocytes were then transfected with miR-17-5p mimics or inhibitors in order to analyze its downstream target. Our results demonstrated that dexrazoxane has a potent effect on preventing cardiac injury induced by doxorubicin in vivo and in vitro by reducing cardiomyocyte apoptosis. MicroRNA plays an important role in cardiovascular diseases. Our data revealed that dexrazoxane could upregulate the expression of miR-17-5p, which plays a cytoprotective role in response to hypoxia by regulating cell apoptosis. Furthermore, the miRNA and protein analysis revealed that miR-17-5p significantly attenuated phosphatase and tensin homolog (PTEN) expression in cardiomyocytes exposed to doxorubicin. Taken together, dexrazoxane might exert a cardioprotective effect against doxorubicin-induced cardiomyocyte apoptosis by regulating the expression of miR-17-5p/PTEN cascade.