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

  • Jingyi ChenEmail author
  • Zhenzhen Jiang
  • Xing Zhou
  • Xingxing Sun
  • Jianwei Cao
  • Yongpan Liu
  • Xianyu Wang


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.


Ischemia/reperfusion Inflammation Necroptosis High-mobility group box-1 Dexmedetomidine 



We thank M. Arico from Liwen Bianji, Edanz Group China (, for editing the English text of a draft of this manuscript.

Authors’ 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.


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

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interests.

Ethical Approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Informed Consent

This article does not contain any studies with human participants performed by any of the authors.


  1. 1.
    Koeppen M, Lee JW, Seo SW, Brodsky KS, Kreth S, Yang IV, et al. Hypoxia-inducible factor 2-alpha-dependent induction of amphiregulin dampens myocardial ischemia-reperfusion injury. Nat Commun. 2018;9:816.CrossRefGoogle Scholar
  2. 2.
    Kawai H, Chaudhry F, Shekhar A, Petrov A, Nakahara T, Tanimoto T, Kim D, Chen J, Lebeche D, Blankenberg FG, et al. Molecular imaging of apoptosis in ischemia reperfusion injury with radiolabeled Duramycin targeting phosphatidylethanolamine: Effective Target Uptake and Reduced Nontarget Organ Radiation Burden. JACC Cardiovasc Imaging. 2018.Google Scholar
  3. 3.
    Ferrari RS, Andrade CF. Oxidative stress and lung ischemia-reperfusion injury. Oxidative Med Cell Longev. 2015;2015:590987.CrossRefGoogle Scholar
  4. 4.
    Chorawala MR, Prakash P, Doddapattar P, Jain M, Dhanesha N, Chauhan AK. Deletion of extra domain a of fibronectin reduces acute myocardial ischaemia/reperfusion injury in hyperlipidaemic mice by limiting thrombo-inflammation. Thromb Haemost. 2018;118:1450–60.CrossRefGoogle Scholar
  5. 5.
    Roberta A, Vicentino R, Carneiro VC, Carneiro VC, Allonso D, Guilherme R, et al. Emerging role of HMGB1 in the pathogenesis of schistosomiasis liver fibrosis. Front Immunol. 2018;9:1979.CrossRefGoogle Scholar
  6. 6.
    Sekiguchi F, Domoto R, Nakashima K, Yamasoba D, Yamanishi H, Tsubota M, et al. Paclitaxel-induced HMGB1 release from macrophages and its implication for peripheral neuropathy in mice: evidence for a neuroimmune crosstalk. Neuropharmacology. 2018;141:201–13.CrossRefGoogle Scholar
  7. 7.
    Loukili N, Rosenblatt-Velin N, Li J, Clerc S, Pacher P, Feihl F, et al. Peroxynitrite induces HMGB1 release by cardiac cells in vitro and HMGB1 upregulation in the infarcted myocardium in vivo. Cardiovasc Res. 2011;89:586–94.CrossRefGoogle Scholar
  8. 8.
    Andrassy M, Volz HC, Igwe JC, Funke B, Eichberger SN, Kaya Z, et al. High-mobility group Box-1 in ischemia-reperfusion injury of the heart. Circulation. 2008;117:3216–26.CrossRefGoogle Scholar
  9. 9.
    In EJ, Lee Y, Koppula S, Kim TY, Han JH, Lee KH, et al. Identification and characterization of NTB451 as a potential inhibitor of necroptosis. Molecules. 2018;23.Google Scholar
  10. 10.
    Xu Z, Jin Y, Yan H, Gao Z, Xu B, Yang B, et al. High-mobility group box 1 protein-mediated necroptosis contributes to dasatinib-induced cardiotoxicity. Toxicol Lett. 2018;296:39–47.CrossRefGoogle Scholar
  11. 11.
    Galluzzi L, Kepp O, Chan FK, Kroemer G. Necroptosis: mechanisms and relevance to disease. Annu Rev Pathol. 2017;12:103–30.CrossRefGoogle Scholar
  12. 12.
    Abdel-Ghaffar HS, Kamal SM, El Sherif FA, Mohamed SA. Comparison of nebulised dexmedetomidine, ketamine, or midazolam for premedication in preschool children undergoing bone marrow biopsy. Br J Anaesth. 2018;121:445–52.CrossRefGoogle Scholar
  13. 13.
    Peng K, Qiu Y, Li J, Zhang ZC, Ji FH. Dexmedetomidine attenuates hypoxia/reoxygenation injury in primary neonatal rat cardiomyocytes. Exp Ther Med. 2017;14:689–95.CrossRefGoogle Scholar
  14. 14.
    Zhang JJ, Peng K, Zhang J, Meng XW, Ji FH. Dexmedetomidine preconditioning may attenuate myocardial ischemia/reperfusion injury by down-regulating the HMGB1-TLR4-MyD88-NF-small ka, CyrillicB signaling pathway. PLoS One. 2017;12:e0172006.CrossRefGoogle Scholar
  15. 15.
    Meng L, Li L, Lu S, Li K, Su Z, Wang Y, et al. The protective effect of dexmedetomidine on LPS-induced acute lung injury through the HMGB1-mediated TLR4/NF-kappaB and PI3K/Akt/mTOR pathways. Mol Immunol. 2018;94:7–17.CrossRefGoogle Scholar
  16. 16.
    Deng F, Wang S, Cai S, Hu Z, Xu R, Wang J, et al. Inhibition of caveolae contributes to propofol preconditioning-suppressed microvesicles release and cell injury by hypoxia-reoxygenation. Oxidative Med Cell Longev. 2017;2017:3542149.CrossRefGoogle Scholar
  17. 17.
    Deng F, Wang S, Zhang L, Xie X, Cai S, Li H, et al. Propofol through upregulating caveolin-3 attenuates post-hypoxic mitochondrial damage and cell death in H9C2 cardiomyocytes during hyperglycemia. Cell Physiol Biochem. 2017;44:279–92.CrossRefGoogle Scholar
  18. 18.
    Muller T, Dewitz C, Schmitz J, Schroder AS, Brasen JH, Stockwell BR, et al. Necroptosis and ferroptosis are alternative cell death pathways that operate in acute kidney failure. Cell Mol Life Sci. 2017;74:3631–45.CrossRefGoogle Scholar
  19. 19.
    McDonald KA, Huang H, Tohme S, Loughran P, Ferrero K, Billiar T, et al. Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling. Mol Med. 2015;20:639–48.Google Scholar
  20. 20.
    Mersmann J, Iskandar F, Latsch K, Habeck K, Sprunck V, Zimmermann R, et al. Attenuation of myocardial injury by HMGB1 blockade during ischemia/reperfusion is toll-like receptor 2-dependent. Mediat Inflamm. 2013;2013:174168.CrossRefGoogle Scholar
  21. 21.
    Tong S, Zhang L, Joseph J, Jiang X. Celastrol pretreatment attenuates rat myocardial ischemia/ reperfusion injury by inhibiting high mobility group box 1 protein expression via the PI3K/Akt pathway. Biochem Biophys Res Commun. 2018;497:843–9.CrossRefGoogle Scholar
  22. 22.
    Sun HJ, Lu Y, Wang HW, Zhang H, Wang SR, Xu WY, et al. Activation of endocannabinoid receptor 2 as a mechanism of propofol pretreatment-induced cardioprotection against ischemia-reperfusion injury in rats. Oxidative Med Cell Longev. 2017;2017:2186383.Google Scholar
  23. 23.
    Sun Y, Jiang C, Jiang J, Qiu L. Dexmedetomidine protects mice against myocardium ischaemic/reperfusion injury by activating an AMPK/PI3K/Akt/eNOS pathway. Clin Exp Pharmacol Physiol. 2017;44:946–53.CrossRefGoogle Scholar
  24. 24.
    Chen Z, Ding T, Ma CG. Dexmedetomidine (DEX) protects against hepatic ischemia/reperfusion (I/R) injury by suppressing inflammation and oxidative stress in NLRC5 deficient mice. Biochem Biophys Res Commun. 2017;493:1143–50.CrossRefGoogle Scholar
  25. 25.
    Nishida K, Otsu K. Autophagy during cardiac remodeling. J Mol Cell Cardiol. 2016;95:11–8.CrossRefGoogle Scholar
  26. 26.
    Frank D, Vince JE. Pyroptosis versus necroptosis: similarities, differences, and crosstalk. Cell Death Differ. 2018.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Anesthesiology, Taihe HospitalHubei University of MedicineShiyanChina
  2. 2.Institute of Anesthesiology, Department of Anesthesiology, Taihe HospitalHubei University of MedicineShiyanChina
  3. 3.Department of Anesthesiology, Renmin HospitalHubei University of MedicineShiyanChina
  4. 4.Department of Ultrasonography Medicine, Taihe HospitalHubei University of MedicineShiyanChina
  5. 5.Department of Orthopedics, Taihe HospitalHubei University of MedicineShiyanChina

Personalised recommendations