心脏毒性是一种抗癌药物的严重不良反应,多柔比星(DOX),这可能发生在一年或几十年后完成治疗。本研究旨在解决有关缺乏能够预测DOX引起的心脏毒性风险的循环生物标志物的知识空白。小鼠血浆中2083个微小RNA(miRNA)的分析显示,在6、9、12、18或24mg/kg总累积DOX剂量(早期发作模型)或盐水(SAL)后1周,有81个差异表达的miRNA。其中,在12mg/kg和更高的累积剂量下,7种miRNA的表达在心肌损伤发作之前发生了改变。与同时的SAL处理的对照相比,在所有总累积剂量下仅miR-34a-5p的表达显著升高(错误发现率[FDR]<0.1),并且显示统计学上显著的剂量相关应答。D0X暴露期间血浆miR-34a-5p表达水平的趋势也与这些小鼠中miR-34a-5p的心脏表达的显著剂量相关增加相关。服用心脏保护药物,右旋雷佐生,DOX治疗前的小鼠,显著减轻血浆和心脏中miR-34a-5p的表达,同时减轻心脏病理.血浆和心脏之间的这种关联可能表明miR-34a-5p是早期发作的DOX心脏毒性的潜在早期循环标志物。此外,在24mg/kg总累积DOX剂量后24周,与SAL治疗的对照组相比,血浆和心脏中miR-34a-5p的表达更高(FDR<0.1),在我们最近建立的延迟发作心脏毒性模型中,当心功能发生改变时,表明其作为迟发性心脏毒性的早期生物标志物的潜力。
Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early-onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR-34a-5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL-treated controls and showed a statistically significant dose-related response. The trend in plasma miR-34a-5p expression levels during DOX exposures also correlated with a significant dose-related increase in cardiac expression of miR-34a-5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR-34a-5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR-34a-5p as a potential early circulating marker of early-onset DOX cardiotoxicity. In addition, higher expression of miR-34a-5p (FDR < 0.1) in plasma and heart compared with SAL-treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed-onset cardiotoxicity model, indicated its potential as an early biomarker of delayed-onset cardiotoxicity.