Department of Cardiovasology, Hunan Provincial People's Hospital, Changsha, Hunan, 410000, People's Republic of China.
Cardiovasc Toxicol. 2021 Apr;21(4):302-313. doi: 10.1007/s12012-020-09620-3. Epub 2021 Feb 27.
Doxorubicin (DOX) is a widely used cytotoxic drug whose application is limited by its severe side effects. Little was known regarding how to offset its side effects. Therefore this study aims to explore the role of miR-200a-3p in DOX-induced cardiotoxicity and its possible mechanism. DOX-induced myocardial injury rat models were established, which were then injected with miR-200a-3p inhibitor (miR-200a-3p suppression) to observe the effects of miR-200a-3p on cell proliferation, and apoptosis. Heart function and weights of rat models were also measured. Cardiomyocytes were induced by DOX, in which PEG3 knockdown or corresponding plasmids were transfected to assess the possible effect of PEG3 on cell activity. Dual luciferase reporter assay was applied to verify the binding of PEG3 with miR-200a-3p. Elevated levels of lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB) and left ventricular end-diastolic pressure (LVEDP), as well as suppressed left ventricular systolic pressure (LVSP) and ± dp/dt were showed in myocardial injury rat models. DOX induced myocardial injury and increased miR-200a-3p expression levels. miR-200a-3p inhibitor could partially attenuate DOX-induced cardiotoxicity in rat models, while PEG3 could regulate myocardial injury in DOX-treated cell models. miR-200a-3p, by targeting PEG3 through SIRT1/NF-κB signal pathway, regulated cell proliferation, inflammation and apoptosis of myocardiocytes. The results in current study demonstrated that miR-200a-3p regulates cell proliferation and apoptosis of cardiomyocytes by targeting PEG3 through SIRT1/NF-κB signal pathway. This result may provide a potential clue for the treatment of DOX-induced cardiotoxicity.
多柔比星（DOX）是一种广泛使用的细胞毒性药物，但其严重的副作用限制了其应用。对于如何抵消其副作用知之甚少。因此，本研究旨在探讨 miR-200a-3p 在 DOX 诱导的心肌毒性中的作用及其可能的机制。建立 DOX 诱导的心肌损伤大鼠模型，然后向模型中注射 miR-200a-3p 抑制剂（miR-200a-3p 抑制），观察 miR-200a-3p 对细胞增殖和凋亡的影响。还测量了大鼠模型的心脏功能和体重。用 DOX 诱导心肌细胞，转染 PEG3 敲低或相应质粒，评估 PEG3 对细胞活性的可能影响。双荧光素酶报告基因实验用于验证 PEG3 与 miR-200a-3p 的结合。乳酸脱氢酶（LDH）、肌酸激酶-MB（CK-MB）和左心室舒张末期压（LVEDP）水平升高，左心室收缩压（LVSP）和±dp/dt 降低，表明心肌损伤大鼠模型存在心肌损伤。DOX 诱导心肌损伤并增加 miR-200a-3p 表达水平。miR-200a-3p 抑制剂可部分减轻 DOX 诱导的大鼠模型中的心脏毒性，而 PEG3 可调节 DOX 处理的细胞模型中的心肌损伤。miR-200a-3p 通过 SIRT1/NF-κB 信号通路靶向 PEG3，调节心肌细胞的增殖、炎症和凋亡。本研究结果表明，miR-200a-3p 通过 SIRT1/NF-κB 信号通路靶向 PEG3，调节心肌细胞的增殖和凋亡。这一结果可能为治疗 DOX 诱导的心脏毒性提供潜在线索。
