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Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway

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Abstract

Background

Rhein, which has antioxidant and anti-inflammatory response properties, is a beneficial treatment for different pathologies. However, the mechanism by which rhein protects against myocardial ischemic injury is poorly understood.

Methods and results

To establish an acute myocardial infarction (AMI) rat model, we performed left anterior descending (LAD) ligation. Sprague‒Dawley rats were randomly divided into four groups: sham, AMI, AMI + rhein (AMI + R), and AMI + mitochondrial fission inhibitor (AMI + M). The extent of myocardial injury was evaluated by TTC staining, serum myocardial injury markers, and HE and Masson staining. Cardiac mitochondria ultrastructure was visualized by transmission electron microscopy. TUNEL assay and flow cytometry analysis were used to estimate cell apoptosis. Protein expression levels were measured by Western blotting. In vitro, the efficacy of rhein was assessed in H9c2 cells under hypoxic condition. Our results revealed that rats with AMI exhibited increased infarct size and indicators of myocardial damage, along with activation of Drp1-dependent mitochondrial fission, decreased mitophagy and increased apoptosis rates. However, pretreatment with rhein significantly reversed these effects and demonstrated similar efficacy to Mdivi-1. Furthermore, rhein pretreatment protected against myocardial ischemic injury by inhibiting mitochondrial fission, as evidenced by decreased Drp1 expression. It also enhanced mitophagy, as indicated by increased expression of Beclin1, Pink1 and Parkin, an increased LC3-II/LC3-I ratio and increased formation of autolysosomes. Additionally, rhein pretreatment mitigated apoptosis in AMI. These results were also confirmed in vitro in H9c2 cells.

Conclusion

Our results demonstrate that rhein pretreatment exerts cardioprotective effects against myocardial ischemic injury via the Drp1/Pink1/Parkin pathway.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We sincerely thank all the colleagues from the National Clinical Research Center of Kidney Diseases in Jinling Hospital for their invaluable assistance and guidance in our experimental techniques. In particular, we thank our colleagues who participated in this study.

Funding

The present study was supported by the National Natural Science Foundation of China (Grant Number 81400238) and Basic Research Programs of Jinling Hospital, China (Grant Number 22JCYYYB46).

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Author notes

  1. Hanqing Li and Yan Jia have contributed equally to this work and are first authors.

Authors and Affiliations

  1. Department of Cardiology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, 305 East Zhong Shan Rd, Nanjing, 210002, China

    Hanqing Li, Yan Jia, Lijun Wang & Jing Liu

  2. Department of Pharmacology, Nanjing University of Chinese Medicine, Nanjing, 210023, China

    Daomin Yao

  3. Department of Pharmacy, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, 305 East Zhong Shan Rd, Nanjing, 210002, China

    Ming Gao

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  1. Hanqing Li
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  4. Ming Gao
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Contributions

JL, LW, MG and HL conceptualized and participated in the overall design, supervision and coordination of the study. HL, YJ and DY designed and performed most of the experiments. The first draft of the manuscript was written by HL and all authors commented on previous versions of the manuscript. LW revised of the manuscript. All the authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Ming Gao, Lijun Wang or Jing Liu.

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The authors have no relevant financial or nonfinancial interests to declare.

Ethical approval

Our study was carried out as per recommendations from the Animal Ethical Committee of Jinling Hospital (Approval No. 2021DZGKJDWLS-0042) strictly following the guidelines of National Institutes of Health (NIH) for the Care and Use of Laboratory Animals.

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Li, H., Jia, Y., Yao, D. et al. Rhein alleviates myocardial ischemic injury by inhibiting mitochondrial division, activating mitochondrial autophagy and suppressing myocardial cell apoptosis through the Drp1/Pink1/Parkin pathway. Mol Biol Rep 51, 266 (2024). https://doi.org/10.1007/s11033-023-09154-1

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