Protective role of Quercetin on Pink1 / Parkin-dependent mitophagy against doxorubicin-induced cardiotoxicity
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Department of Cardiovascular Surgery, Xijing Hospital, Air Force Medical University, Xi’an 710032, China

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R-33

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    Abstract:

    Objective The clinical application of doxorubicin ( Dox ) is limited by its dose-dependent cardiotoxicity. This study was established to elucidate the mechanism by which Quercetin ( Que) acts in Dox-induced cytotoxicity. Methods Mice were randomly divided into a Con group, Que group, Dox group and Dox-Que group. Neonatal mouse cardiomyocytes were isolated and randomly divided into a Dox-Vehicle group, Dox-Que group, Dox-Que-SB group, Dox-SB group and Dox-3 MA group. Cell viability was detected by CCK-8 kit, while ATP content and ROS production were determined simultaneously. In addition, Western blot was used to determine the expression of mitophagy marker proteins. Results In vivo studies confirmed that Que can reduce Dox-induced cardiotoxicity by inhibiting mitophagy and reducing myocardial fibrosis. In vitro studies showed that Dox treatment significantly reduced the cell activity of neonatal mouse cardiomyocytes and ATP content, increased ROS production, and significantly activated mitophagy (P< 0.05). Que pretreatment alleviated Dox-induced cardiomyocyte injury by inhibiting the activation of mitophagy while reducing ROS production and increasing mitochondrial ATP content. Our study further confirmed that the inhibitory effect of Que on mitophagy was mediated by the Pink1 / Parkin-dependent signaling pathway, and that SB treatment partially offset the protective effect of Que on Dox-induced cardiotoxicity by activating mitophagy. Conclusions Que can inhibit Pink1 / Parkin-mediated mitophagy activation, promote ATP production, reduce ROS production and alleviate Dox-induced cardiotoxicity.

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History
  • Received:March 14,2021
  • Revised:
  • Adopted:
  • Online: November 09,2022
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