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Metformin confers longitudinal cardiac protection by preserving mitochondrial homeostasis following myocardial ischemia/reperfusion injury

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Abstract

Purpose

Myocardial ischemia–reperfusion (I/R) injury is associated with systemic oxidative stress, cardiac mitochondrial homeostasis, and cardiomyocyte apoptosis. Metformin has been recognized to attenuate cardiomyocyte apoptosis. However, the longitudinal effects and pathomechanism of metformin on the regulation of myocardial mitohormesis following I/R treatment remain unclear. This study aimed to investigate the longitudinal effects and mechanism of metformin in regulating cardiac mitochondrial homeostasis by serial imaging with the 18-kDa translocator protein (TSPO)–targeted positron emission tomography (PET) tracer 18F-FDPA.

Methods

Myocardial I/R injury was established in Sprague–Dawley rats, which were treated with or without metformin (150 mg/kg per day). Serial gated 18F-FDG and 18F-FDPA PET imaging were performed at 1, 4, and 8 weeks after surgery, followed by analysis of ventricular remodelling and cardiac mitochondrial homeostasis. The correlation between Hsp60 and 18F-FDPA uptake was analyzed. After PET imaging, the activity of antioxidant enzymes, immunostaining, and western blot analysis were performed to analyze the spatio-temporal effects and pathomechanism of metformin for cardiac protection after myocardial I/R injury.

Results

Oxidative stress and apoptosis increased 1 week after myocardial I/R injury (before significant progression of ventricular remodelling). TSPO expression was correlated with Hsp60 expression and was co-localized with inflammatory CD68+ macrophages in the infarct area, and TSPO uptake was associated with an upregulation of AMPK-p/AMPK and a downregulation of Bcl-2/Bax. However, these effects were reversed with metformin treatment. Eight weeks after myocardial I/R injury (representing the advanced stage of heart failure), 18F-FDPA uptake in myocardial cells in the distal non-infarct area increased without CD68+ expression, whereas the activity decreased with metformin treatment.

Conclusion

Taken together, these results show that a prolonged metformin treatment has pleiotropic protective effects against myocardial I/R injury associated with a regional and temporal dynamic balance between mitochondrial homeostasis and cardiac outcome, which were assessed by TSPO-targeted imaging during cardiac remodelling.

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Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 81871377, 81571717, 82171994) and Beijing Municipal Administration of Hospitals (ZYLX202110) .

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  1. Jing Tian and Yaqi Zheng have contributed equally to the manuscript.

Authors and Affiliations

  1. Department of Nuclear Medicine, Molecular Imaging Lab, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Jing Tian, Yaqi Zheng, Tiantian Mou, Mingkai Yun, Yi Tian, Yao Lu, Yujie Bai, Yihan Zhou, Xiaoli Zhang & Xiang Li

  2. Division of Nuclear Medicine, Department of Biomedical Imaging and Image-Guided Therapy, Vienna General Hospital, Medical University of Vienna, Vienna, Austria

    Marcus Hacker & Xiang Li

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Contributions

Jing Tian and Xiaoli Zhang designed the study. Tiantian Mou carried out the radiolabelling experiments. Yi Tian, Jing Tian, and Yaqi Zheng performed the animal experiments. Jing Tian, Xiang Li, and Mingkai Yun interpreted and analysed the scans. Jing Tian analyzed and interpreted the data. Jing Tian wrote the first draft of manuscript, which was revised by Marcus Hacker, Xiaoli Zhang, and Xiang Li. All authors read and approved the final manuscript.

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Correspondence to Xiaoli Zhang or Xiang Li.

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All animal experiments were performed according to Beijing’s laboratory animal management regulations and were approved by the Animal Care Committee of Capital Medical University (Ethical approval number: AEEI-2019–167).

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Tian, J., Zheng, Y., Mou, T. et al. Metformin confers longitudinal cardiac protection by preserving mitochondrial homeostasis following myocardial ischemia/reperfusion injury. Eur J Nucl Med Mol Imaging 50, 825–838 (2023). https://doi.org/10.1007/s00259-022-06008-z

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