MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2.
MicroRNA-140-5p aggravates doxorubicin-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2.
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DOI：
10.1016/j.redox.2017.12.013
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发表时间：
2018-05
期刊：
影响因子：
11.4
通讯作者：
Peng J
中科院分区：
文献类型：
--
作者：
Zhao L;Qi Y;Xu L;Tao X;Han X;Yin L;Peng J
多柔比星（DOX）是一种蒽环类抗生素，具有很强的抗肿瘤作用，但由于其心脏毒性，其临床应用受到限制.然而，其发病机制仍不完全清楚。本文旨在探讨阿霉素心脏毒性的作用机制和新的药物靶点。建立了H9 C2细胞的体外模型以及大鼠和小鼠的体内模型。结果表明，DOX可显著降低H9 C2细胞活力，升高CK、LDH水平，引起大鼠和小鼠心肌组织病理学和心电图改变，并通过调节细胞内ROS、MDA、SOD、GSH和GSH-Px水平而引发心肌氧化损伤。利用microRNA微阵列技术筛选出18条DOX诱导的大鼠心肌组织差异表达的microRNA，特别是miR-140- 5 p在DOX诱导下表达显著增加，并将其作为靶miRNA。双荧光素酶报告基因检测结果显示，miR-140- 5 p可直接靶向Nrf 2和Sirt 2，影响HO-1、NQO 1、Gst、GCLM、Keap 1和FOXO 3a的表达水平，从而增加DOX对心肌的氧化损伤。此外，在miR-140- 5 p模拟物或miR-140- 5 p抑制剂转染后，用DOX处理的H9 C2细胞中细胞内ROS水平分别显著增加或减少，以及Nrf 2和Sirt 2的表达水平改变。此外，DOX诱导的心肌氧化损伤在用miR-140- 5 p阿戈米尔处理的小鼠中恶化，而在施用miR-140- 5 p阿戈米尔的小鼠中损伤减轻。因此，miR-140- 5 p通过靶向Nrf 2和Sirt 2促进心肌氧化应激，在DOX诱导的心脏毒性中发挥重要作用。我们的数据为研究DOX诱导的心脏损伤提供了新的见解。此外，miR-140- 5 p/Nrf 2和miR-140- 5 p/Sirt 2可能成为治疗DOX心脏毒性的新靶点。DOX在体外和体内显著增加miR-140- 5 p的水平。MiR-140- 5 p加重了DOX诱导的心脏毒性。miR-140- 5 p促进心肌氧化应激。miR-140- 5 p直接靶向Nrf 2和Sirt 2。miR-140- 5 p可能是DOX心脏毒性的新靶点。
Clinical application of doxorubicin (DOX), an anthracycline antibiotic with potent anti- tumor effects, is limited because of its cardiotoxicity. However, its pathogenesis is still not entirely understood. The aim of this paper was to explore the mechanisms and new drug targets to treat DOX-induced cardiotoxicity. The in vitro model on H9C2 cells and the in vivo models on rats and mice were developed. The results showed that DOX markedly decreased H9C2 cell viability, increased the levels of CK, LDH, caused histopathological and ECG changes in rats and mice, and triggered myocardial oxidative damage via adjusting the levels of intracellular ROS, MDA, SOD, GSH and GSH-Px. Total of 18 differentially expressed microRNAs in rat heart tissue caused by DOX were screened out using microRNA microarray assay, especially showing that miR-140-5p was significantly increased by DOX which was selected as the target miRNA. Double-luciferase reporter assay showed that miR-140-5p directly targeted Nrf2 and Sirt2, as a result of affecting the expression levels of HO-1, NQO1, Gst, GCLM, Keap1 and FOXO3a, and thereby increasing DOX-caused myocardial oxidative damage. In addition, the levels of intracellular ROS were significantly increased or decreased in H9C2 cells treated with DOX after miR-140-5p mimic or miR-140-5p inhibitor transfection, respectively, as well as the changed expression levels of Nrf2 and Sirt2. Furthermore, DOX- induced myocardial oxidative damage was worsened in mice treated with miR-140-5p agomir, and however the injury was alleviated in the mice administrated with miR-140-5p antagomir. Therefore, miR-140-5p plays an important role in DOX-induced cardiotoxicity by promoting myocardial oxidative stress via targeting Nrf2 and Sirt2. Our data provide novel insights for investigating DOX-induced heart injury. In addition, miR-140-5p/ Nrf2 and miR-140-5p/Sirt2 may be the new targets to treat DOX-induced cardiotoxicity. DOX significantly increased the levels of miR-140-5p in vitro and in vivo. MiR-140-5p aggravated DOX-induced cardiotoxicity. MiR-140-5p promoted myocardial oxidative stress. MiR-140-5p directly targeted Nrf2 and Sirt2. MiR-140-5p may be the new target of DOX-induced cardiotoxicity.
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DOI：
10.3904/kjim.2016.017
发表时间：
2016-07
期刊：
The Korean journal of internal medicine
影响因子：
--
作者：
Chung WB;Youn HJ
通讯作者：
Youn HJ
影响因子：
4.7
作者：
Luo, Cheng;Urgard, Egon;Metspalu, Andres
通讯作者：
Metspalu, Andres
DOI：
10.1161/circheartfailure.115.002661
发表时间：
2016-01
期刊：
Circulation. Heart failure
影响因子：
--
作者：
Bloom MW;Hamo CE;Cardinale D;Ky B;Nohria A;Baer L;Skopicki H;Lenihan DJ;Gheorghiade M;Lyon AR;Butler J
通讯作者：
Butler J
影响因子：
5
作者：
Li, Dan L.;Hill, Joseph A.
通讯作者：
Hill, Joseph A.
影响因子：
5.1
作者：
Elsherbiny, Nehal M.;Salama, Mohamed F.;Al-Gayyar, Mohammed M. H.
通讯作者：
Al-Gayyar, Mohammed M. H.