MiR-125b enhances doxorubicin-induced cardiotoxicity by suppressing the nucleus-cytoplasmic translocation of YAP via targeting STARD13

ENVIRONMENTAL TOXICOLOGY(2022)

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摘要
The clinical application of doxorubicin (Dox) is limited due to its cardiotoxicity, while the pathogenesis remains to be fully understood. Recent studies have suggested that microRNA (miRNA) plays an important role in Dox-induced cardiotoxicity. This work aims to investigate the effects of miR-125b in Dox-induced cardiotoxicity. Here, mice model combined with cell line analysis were used, and cell viability assay, detection of reactive oxygen species (ROS), malondialdehyde (MDA) activity, lactate dehydrogenase (LDH) activity, glutathione (GSH) level, glutathione peroxidase (GSH-Px) level, superoxide dismutase (SOD) activity, and histopathological changes were performed to characterize miR-125b effects; real-time quantitative polymerase chain reaction (PCR), luciferase reporter assay, RNA immunoprecipitation, and western blot analysis were subjected to reveal the underlying mechanisms. It was found that miR-125b level was upregulated in myocardial cell line H9C2 treated with Dox and miR-125b overexpression enhanced Dox-induced cytotoxicology of H9C2 cells, while miR-125b inhibition exhibited a protective effect by measuring ROS level and cell viability. In consistent, in vivo experiments with miR-125b agomir or antagomir obtained a consistent result through examining the activity of MDA, LDH, GSH, GSH-Px, SOD, and histopathological changes. Furthermore, we found that miR-125b could target STARD13 and thus suppressed the nucleus-cytoplasmic translocation of yes-associated protein (YAP). Additionally, this STARD13/YAP axis is necessary for miR-125b-mediated regulation on Dox-induced cytotoxicology of H9C2 cells. In conclusion, our study demonstrated that miR-125b could enhance Dox-induced cardiotoxicity through targeting the STARD13/YAP axis.
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关键词
cardiotoxicity, doxorubicin, MiR-125b, STADR13, YAP
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