Department of Genetics, Faculty of Science, Shahid Chamran University of Ahvaz, Ahvaz, Iran.
Department of Biology, Faculty of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
Cell Death Dis. 2018 Jul 9;9(7):758. doi: 10.1038/s41419-018-0797-1.
Doxorubicin (Dox) is a widely used powerful chemotherapeutic component for cancer treatment. However, its clinical application has been hampered due to doxorubicin-induced cardiomyopathy upon the cessation of chemotherapy. Previous studies revealed that PPARγ plays a crucial protective role in cardiomyocytes. Modulation of miRNA expression is an applicable approach for prohibition of toxicity induction. Therefore, the aim of present study is uprising of PPARγ transcript levels via manipulation of miRNAs to limit Dox-induced cardiotoxicity in mESCs-derived cardiac cells, as in vitro model cell to provide a simple direct approach for further clinical therapies. Based on bioinformatics data mining, eventually miR-130a was selected to target PPARγ. This miRNA is highly expressed in heart. The expression of miR-130a increases sharply upon Dox treatment while specific antagomiR-130a reverses Dox-induced reduced expression of PPARγ, cellular apoptosis, and inflammation. Our data strongly suggest that antagomiR-130a limits Dox-induced cellular toxicity via PPARγ upregulation and may have clinical relevance to limit in vivo Dox toxicity.
阿霉素（Dox）是一种广泛用于癌症治疗的强力化疗药物成分。然而，由于化疗停止后会引发阿霉素诱导性心肌病，其临床应用受到了限制。先前的研究表明，PPARγ在心肌细胞中起着至关重要的保护作用。miRNA 表达的调节是一种防止毒性诱导的可行方法。因此，本研究旨在通过操纵 miRNA 来提高 PPARγ 的转录水平，以限制 mESCs 衍生的心肌细胞中的 Dox 诱导的心脏毒性，作为体外模型细胞，为进一步的临床治疗提供一种简单直接的方法。基于生物信息学数据挖掘，最终选择 miR-130a 作为 PPARγ 的靶点。这种 miRNA 在心脏中高度表达。在 Dox 处理后，miR-130a 的表达急剧增加，而特异性 antagomiR-130a 则逆转了 Dox 诱导的 PPARγ 表达减少、细胞凋亡和炎症。我们的数据强烈表明，antagomiR-130a 通过上调 PPARγ 限制了 Dox 诱导的细胞毒性，并且可能与限制体内 Dox 毒性具有临床相关性。
