The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Beijing Hospital, National Center of Gerontology, National Health Commission, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing 100730, China.
Peking University Fifth School of Clinical Medicine, Beijing 100730, China.
Biomed Res Int. 2020 Mar 1;2020:5107193. doi: 10.1155/2020/5107193. eCollection 2020.
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.
多柔比星在临床应用中因其致命的心脏毒性而受到限制。右雷佐生是唯一被 FDA 批准用于预防多柔比星诱导的心脏毒性的心脏保护药物。然而，右雷佐生的作用机制尚不完全清楚。我们的研究旨在探讨右雷佐生对抗多柔比星诱导的心脏毒性的可能分子机制。我们建立了多柔比星诱导的小鼠和心肌细胞损伤模型。雄性 C57BL/6J 小鼠随机分为对照组（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）。进行超声心动图和组织学分析以评估心脏功能和结构。在体外，用右雷佐生处理 DOX 处理的心肌细胞，进行 DNA 梯带、qRT-PCR 和 Western blot 分析。然后将 miR-17-5p 模拟物或抑制剂转染到心肌细胞中，以分析其下游靶标。我们的结果表明，右雷佐生通过减少心肌细胞凋亡，在体内和体外均具有预防多柔比星诱导的心脏损伤的有效作用。microRNA 在心血管疾病中发挥重要作用。我们的数据表明，右雷佐生可以上调 miR-17-5p 的表达，通过调节细胞凋亡，在缺氧时发挥细胞保护作用。此外，miRNA 和蛋白质分析表明，miR-17-5p 可显著降低多柔比星处理的心肌细胞中磷酸酶和张力蛋白同源物（PTEN）的表达。综上所述，右雷佐生可能通过调节 miR-17-5p/PTEN 级联表达，发挥对多柔比星诱导的心肌细胞凋亡的心脏保护作用。
