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Dexmedetomidine post-conditioning alleviates myocardial ischemia–reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation

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Abstract

The SLC7A11/GPX4 axis plays an important role in ferroptosis during cardiac ischemia/reperfusion injury (IRI). The present study was designed to evaluate the impact of dexmedetomidine (DEX) post-conditioning on cardiac IRI and to explore whether the effect was achieved by SLC7A11/GPX4 signaling pathway regulation. Rat myocardial IRI was established by occluding the left anterior descending artery for 30 min followed by 2-h reperfusion. The infarct area was detected by diphenyltetrazolium chloride (TTC) staining; the cardiac function was evaluated by echocardiography. The levels of lipid peroxide biomarkers were measured to estimate the injury caused by lipid peroxide. HE staining and Sirius staining were utilized to assess myocardial damage and fibrosis. The mitochondrial morphology was observed by electron micrography. Western blot and quantitative real-time polymerase chain reaction were employed to measure the relative molecular characteristics. Our results showed that DEX administration at the beginning of reperfusion attenuated IRI-induced myocardial injury, alleviated mitochondrial dysfunction, decreased the level of reactive oxygen species (ROS), alleviated mitochondrial dysfunction, inhibited the activation of SLC7A11/GPX4, and modulated the expression of ferroptosis-related proteins, including SLC7A11, glutathione peroxidase 4 (GPX4), ferritin heavy chain (FTH), and cyclooxygenase-2 (COX-2). Conversely, the ferroptosis activator erastin partly suppressed the DEX-mediated cardio protection. Altogether, these results reveal that DEX inhibits ferroptosis by enhancing the expression of SLC7A11 and GPX4, thereby preventing cardiac I/R injury.

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Acknowledgements

This study was supported by grants from Jiangsu Province department of science and technology (BE2020634, BK20191138 to J.Z), Top Talent Support Program for young and middle-aged people of Wuxi Health Committee (BJ2020049 to J.Z), the Natural Science Foundation in Jiangxi Province grant (20192ACBL21037 to P.Y.), the National Natural Science Foundation of China (81760048 to J.Z. and 81760050 to P.Y.)

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  1. Peng Yu and Jing Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology and Metabolism, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China

    Peng Yu, Pingping Yang & Shuchun Yu

  2. Department of Anesthesiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China

    Jing Zhang

  3. Department of Anesthesiology, Affiliated Hospital of Jiangnan University, No. 1000, Hefeng Road, Wuxi, 214125, China

    Yi Ding, Dandan Chen & Jiru Zhang

  4. State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, China

    Haijian Sun

  5. Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangnan University, Wuxi, 214125, China

    Fenglai Yuan

  6. Grade 2017, The Second Clinical Medical College of Nanchang University, Nanchang, 330006, China

    Siyuan Li

  7. Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, Jiangxi, China

    Xiaozhong Li & Linghua Fu

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Contributions

PY, JZ, JRZ, YD, DDC, HJS, FLY, SYL, XZL, PPL, LHF, and SCY performed nearly all the experiments. PY, JZ, YD, and DDC performed hemodynamic study and analyzed the data. PY, JZ, and JRZ designed the whole study. PY, SYL, and XZL were the major contributors in writing the manuscript, and all the experiments were performed under their guidance. All authors read and approved the final manuscript.

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Correspondence to Jiru Zhang.

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Yu, P., Zhang, J., Ding, Y. et al. Dexmedetomidine post-conditioning alleviates myocardial ischemia–reperfusion injury in rats by ferroptosis inhibition via SLC7A11/GPX4 axis activation. Human Cell 35, 836–848 (2022). https://doi.org/10.1007/s13577-022-00682-9

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