Abstract
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.
Highlights
Doxorubicin (Dox) is one of the most commonly used and forceful chemotherapeutic agents in cancer treatment
Due to PPARγ's essential role in preventing Dox-induced cardiotoxicity, we examined whether miRNA-130a-dependent upregulation of PPARγ could reverse the toxicity and apoptosis of mouse embryonic stem cells-derived cardiac cells
Dox-induced cardiotoxicity was testified in mouse embryonic stem cells (mESCs)-derived cardiac cells As previously reported[18] (Supplementary Fig. 1A), mESCs were shifted to spontaneous cardiac cell differentiation (Supplementary Fig. 1B)
Summary
Doxorubicin (Dox) is one of the most commonly used and forceful chemotherapeutic agents in cancer treatment. Even though the underlying molecular and cellular mechanisms are still unclear, various studies suggest that oxidative stress, calcium overload, mitochondrial damage, cardiomyocyte apoptosis, and Official journal of the Cell Death Differentiation Association. Pakravan et al Cell Death and Disease (2018)9:758 size of cardiac infarcts, and enhances the efficiency of cardiac contractility in pig[12]. MicroRNAs (miRNAs) are key players in gene expression regulation by degradation or destabilization of the target mRNAs13. Because miRNAs can affect heart development, function, and disease[14], their alterations may have therapeutic values or may cause adverse effects to aggravate the pathologic condition. Very recently Zhao et al have reported that microRNA-140-5p contributes in doxorubicininduced cardiotoxicity through enhancement of myocardial oxidative stress via targeting NRF2 and SIRT22. On the other hand this group has shown that Dioscin, a natural steroid saponin, alleviates doxorubicin-induced cardiotoxicity via modulation of microRNA-140-5p15
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