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Dexmedetomidine Preconditioning Protects Cardiomyocytes Against Hypoxia/Reoxygenation-Induced Necroptosis by Inhibiting HMGB1-Mediated Inflammation

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Abstract

Myocardial ischemia/reperfusion (I/R) injury is a serious threat to the health of people around the world. Recent evidence has indicated that high-mobility group box-1 (HMGB1) is involved in I/R-induced inflammation, and inflammation can cause necroptosis of cells. Interestingly, dexmedetomidine (DEX) has anti-inflammatory properties. Therefore, we speculated that DEX preconditioning may suppress H/R-induced necroptosis by inhibiting expression of HMGB1 in cardiomyocytes. We found that hypoxia/reoxygenation (H/R) significantly increased cellular damage, as measured by cell viability (100 ± 3.26% vs. 53.33 ± 3.29, p < 0.01), CK-MB (1 vs. 3.25 ± 0.26, p < 0.01), cTnI (1 vs. 2.69 ± 0.31, p < 0.01), inflammation as indicated by TNF-α (1 ± 0.09 vs. 2.57 ± 0.12, p < 0.01), IL-1β (1 ± 0.33 vs. 3.87 ± 0.41, p < 0.01) and IL-6 (1 ± 0.36 vs. 3.60 ± 0.45, p < 0.01), and necroptosis, which were accompanied by significantly increased protein levels of HMGB1. These changes [cellular damage as measured by cell viability (53.33 ± 3.29% vs. 67.59 ± 2.69%, p < 0.01), CK-MB (3.25 ± 0.26 vs. 2.27 ± 0.22, p < 0.01), cTnI (2.69 ± 0.31 vs. 1.90 ± 0.25, p < 0.01), inflammation as indicated by TNF-α (2.57 ± 0.12 vs. 1.75 ± 0.15, p < 0.01), IL-1β (3.87 ± 0.41 vs. 2.09 ± 0.36, p < 0.01) and IL-6 (3.60 ± 0.45 vs. 2.21 ± 0.39, p < 0.01), and necroptosis proteins] were inhibited by DEX preconditioning. We also found that silencing expression of HMGB1 reinforced the protective effects of DEX preconditioning and overexpression of HMGB1 counteracted the protective effects of DEX preconditioning. Thus, we concluded that DEX preconditioning inhibits H/R-induced necroptosis by inhibiting expression of HMGB1 in cardiomyocytes.

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Acknowledgments

We thank M. Arico from Liwen Bianji, Edanz Group China (www.liwenbianji.cn/ac), for editing the English text of a draft of this manuscript.

Funding

This study was supported by Taihe Hospital Science and Technology Project in 2018 to Dr. Chen, Jingyi (grant numbers: 2018JJXM046).

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Authors and Affiliations

  1. Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China

    Jingyi Chen, Xing Zhou, Yongpan Liu & Xianyu Wang

  2. Institute of Anesthesiology, Department of Anesthesiology, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China

    Jingyi Chen, Xing Zhou, Yongpan Liu & Xianyu Wang

  3. Department of Anesthesiology, Renmin Hospital, Hubei University of Medicine, Shiyan, 442000, China

    Zhenzhen Jiang

  4. Department of Ultrasonography Medicine, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China

    Xingxing Sun

  5. Department of Orthopedics, Taihe Hospital, Hubei University of Medicine, Shiyan, 442000, China

    Jianwei Cao

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  1. Jingyi Chen
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Contributions

Jingyi Chen conceived and designed the project. Jingyi Chen performed the experiments with the help of Zhenzhen Jiang, Xing Zhou, Xingxing Sun, Jianwei Cao, Yongpan Liu, and Xianyu Wang. Jingyi Chen wrote the manuscript. All authors discussed the manuscript.

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Correspondence to Jingyi Chen.

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Chen, J., Jiang, Z., Zhou, X. et al. Dexmedetomidine Preconditioning Protects Cardiomyocytes Against Hypoxia/Reoxygenation-Induced Necroptosis by Inhibiting HMGB1-Mediated Inflammation. Cardiovasc Drugs Ther 33, 45–54 (2019). https://doi.org/10.1007/s10557-019-06857-1

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