1. Academic Validation
  2. Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway

Paeonol protects against doxorubicin-induced cardiotoxicity by promoting Mfn2-mediated mitochondrial fusion through activating the PKCε-Stat3 pathway

  • J Adv Res. 2022 Jul 14;S2090-1232(22)00156-4. doi: 10.1016/j.jare.2022.07.002.
Mingge Ding 1 Rui Shi 2 Feng Fu 3 Man Li 4 Dema De 5 Yanyan Du 4 Zongfang Li 6
Affiliations

Affiliations

  • 1 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Center for Tumor and Immunology, the Precision Medical Institute, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, Shaanxi 710004, China; Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
  • 2 Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 3 Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
  • 4 Department of Physiology and Pathophysiology, Fourth Military Medical University, Xi'an, Shaanxi 710032, China; School of Life Science, Northwest University, Xi'an, Shaanxi, 710069, China.
  • 5 Department of Geriatrics Cardiology, The Second Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China.
  • 6 National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, China; Center for Tumor and Immunology, the Precision Medical Institute, the Second Affiliated Hospital of Xi' an Jiaotong University, Xi'an, Shaanxi 710004, China. Electronic address: lzf2568@mail.xjtu.edu.cn.
Abstract

Introduction: The anti-cancer medication doxorubicin (Dox) is largely restricted in clinical usage due to its significant cardiotoxicity. The only medication approved by the FDA for Dox-induced cardiotoxicity is dexrazoxane, while it may reduce the sensitivity of Cancer cells to chemotherapy and is restricted for use. There is an urgent need for the development of safe and effective medicines to alleviate Dox-induced cardiotoxicity.

Objectives: The objective of this study was to determine whether Paeonol (Pae) has the ability to protect against Dox-induced cardiotoxicity and if so, what are the underlying mechanisms involved.

Methods: Sprague-Dawley rats and primary cardiomyocytes were used to create Dox-induced cardiotoxicity models. Pae's effects on myocardial damage, mitochondrial function, mitochondrial dynamics and signaling pathways were studied using a range of experimental methods.

Results: Pae enhanced Mfn2-mediated mitochondrial fusion, restored mitochondrial function and cardiac performance both in vivo and in vitro under the Dox conditions. The protective properties of Pae were blunted when Mfn2 was knocked down or knocked out in Dox-induced cardiomyocytes and hearts respectively. Mechanistically, Pae promoted Mfn2-mediated mitochondria fusion by activating the transcription factor STAT3, which bound to the Mfn2 promoter in a direct manner and up-regulated its transcriptional expression. Furthermore, molecular docking, surface plasmon resonance and co-immunoprecipitation studies showed that Pae's direct target was PKCε, which interacted with STAT3 and enabled its phosphorylation and activation. Pae-induced STAT3 phosphorylation and Mfn2-mediated mitochondrial fusion were inhibited when PKCε was knocked down. Furthermore, Pae did not interfere with Dox's antitumor efficacy in several tumor cells.

Conclusion: Pae protects the heart against Dox-induced damage by stimulating mitochondrial fusion via the PKCε-Stat3-Mfn2 pathway, indicating that Pae might be a promising therapeutic therapy for Dox-induced cardiotoxicity while maintaining Dox's Anticancer activity.

Keywords

Doxorubicin; Mfn2; Mitochondrial fusion; PKCε; Paeonol; Stat3.

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