4.7 Article

Harpagoside Protects Against Doxorubicin-Induced Cardiotoxicity via P53-Parkin-Mediated Mitophagy

期刊

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fcell.2022.813370

关键词

p53; parkin; mitophagy; mitochondria; doxorubicin; cardiotoxicity; harpagoside

资金

  1. National Natural Science Foundation of China [81822049, 81673712, 8193000257, 81673802, 82174364]
  2. Major New Drug Creation of Ministry of Science and Technology [2019ZX09201004-001-011]
  3. Fundamental Research Funds for the Central Universities (Distinguished project)
  4. Excellent Young Scientist Foundation of BUCM [BUCM-2019-JCRC005]

向作者/读者索取更多资源

Doxorubicin is an effective chemotherapeutic agent, but its clinical use is limited due to the severe risk of cardiotoxicity. This study finds that harpagoside has significant cardioprotective effects in DICT mouse and rat cardiomyocytes by targeting the interaction between p53 and Parkin to restore mitophagy.
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the hallmarks of doxorubicin-induced cardiotoxicity (DICT) is the cascade of mitophagy deficiency-mitochondrial oxidative injury-apoptosis, while so far, there is no preventive strategy for alleviating DICT by targeting this molecular mechanism. Excitedly, based on our previous drug screen in DICT zebrafish model, harpagoside (HAR) showed dramatic anti-DICT efficacy superior to dexrazoxane (DXZ) only cardioprotectant approved by FDA. Therefore, its pharmacological effects and molecular mechanism on DICT mouse and rat cardiomyocytes were further discussed. In vivo, HAR significantly improved cardiac function and myocardial structural lesions with concomitant of diminished mitochondrial oxidative damage and recovered mitophagy flux. In parallel, HAR protected mitophagy and mitochondria homeostasis, and repressed apoptosis in vitro. Intriguingly, both nutlin-3 (agonist of p53) and Parkin siRNA reversed these protective effects of HAR. Additional data, including fluorescence colocalization of Parkin and MitoTracker and mt-Keima for the detection of mitophagy flux and coimmunoprecipitation of p53 and Parkin, showed that HAR promoted Parkin translocation to mitochondria and substantially restored Parkin-mediated mitophagy by inhibiting the binding of p53 and Parkin. Importantly, the results of the cell viability demonstrated that cardioprotective effect of HAR did not interfere with anticancer effect of DOX on MCF-7 and HepG2 cells. Our research documented p53-Parkin-mediated cascade of mitophagy deficiency-mitochondrial dyshomeostasis-apoptosis as a pathogenic mechanism and druggable pathway and HAR as a cardioprotection on DICT by acting on novel interaction between p53 and Parkin.

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