, Volume 22, Issue 5, pp 662–671 | Cite as

Remifentanil postconditioning ameliorates histone H3 acetylation modification in H9c2 cardiomyoblasts after hypoxia/reoxygenation via attenuating endoplasmic reticulum stress

  • Manli Chen
  • Qin Liu
  • Lijian Chen
  • Lei Zhang
  • Erwei GuEmail author


Remifentanil postconditioning (RPC) elicits cardioprotection against ischemia/reperfusion injury (IRI) by attenuating apoptosis associated with endoplasmic reticulum stress (ERS). Histone H3, acetylation modifications of histone H3, and histone deacetylases (HDAC) also have key roles in the mediation of the survival and apoptosis of cardiomyocytes. In this study, an in vitro IRI model was established with H9c2 cardiomyoblasts to investigate the role of histone H3 acetylation and HDAC3 in RPC-induced attenuation of ERS-associated apoptosis. Briefly, H9c2 cardiomyoblasts were randomly subjected to hypoxia/reoxygenation with and without remifentanil administered at the onset of reoxygenation. Results showed that RPC increased cell viability and prevented cell apoptosis (evidenced by CCK-8 cell viability assays and flow cytometry), and these effects were accompanied by lower levels of expression of GRP78, CHOP, cleaved caspase-12, and cleaved caspase-3. RPC also mimicked the effects of SAHA by increasing the amount of histone H3 deacetylation and decreasing up-regulation of HDAC at both the mRNA and protein levels in response to HR. Finally, RPC-induced protective effects against HR, including attenuation of ERS-associated protein markers, deacetylation of histone H3, and down-regulation of HDAC3 were completely abolished by pretreatment with thapsigargin (TG, a specific ERS activator). In contrast, these effects were not found to be enhanced after pretreatment with 4-phenyl butyric acid (4-PBA, a widely used ERS inhibitor). The present results demonstrate that RPC protects H9c2 cardiomyoblasts from HR injury, and this protection involves an attenuation of ERS-associated apoptosis, which mediates a reduction in HDAC3 expression and an increase in histone H3 deacetylation.


Cardioprotection Remifentanil postconditioning Endoplasmic reticulum stress Histone 3 HDAC3 Apoptosis 



We thank LetPub ( for its linguistic assistance during the preparation of this manuscript.

Authors contributions

EG and MC designed experiments; MC and QL carried out experiments; LC analyzed experimental results. LZ analyzed sequencing data and developed analysis tools. MC wrote the manuscript and EG approved the final manuscript.


The funding was provided by the Key Research Project of education department of Anhui Province (No. KJ2013A161) and the Natural Science Foundation of China (No. 81341014).

Supplementary material

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Supplementary material 1 (TIF 204823 KB)
10495_2017_1347_MOESM2_ESM.tif (188.9 mb)
Supplementary material 2 (TIF 193431 KB)


  1. 1.
    Xia Z, Li H, Irwin MG (2016) Myocardial ischaemia reperfusion injury: the challenge of translating ischaemic and anaesthetic protection from animal models to humans. Br J Anaesth 117(suppl 2):ii44–ii62. doi: 10.1093/bja/aew267 CrossRefPubMedGoogle Scholar
  2. 2.
    Tanaka K, Kersten JR, Riess ML (2014) Opioid-induced cardioprotection. Curr Pharm Des 20(36):5696–5705CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Irwin MG, Wong GT (2015) Remifentanil and opioid-induced cardioprotection. J Cardiothorac Vasc Anesth 29(Suppl 1):S23–S26. doi: 10.1053/j.jvca.2015.01.021 CrossRefPubMedGoogle Scholar
  4. 4.
    Cimen NK, Kosem B, Cimen T, Kartal S, Muslu B, Karabayirli S, Gozdemir M, Kilinc H (2016) Effects of remifentanil, nitroglycerin, and sevoflurane on the corrected QT and Tp-e intervals during controlled hypotensive anesthesia. J Clin Anesth 33:365–372. doi: 10.1016/j.jclinane.2016.04.048 CrossRefPubMedGoogle Scholar
  5. 5.
    Rasmussen LA, Ryhammer PK, Greisen J, Bhavsar RR, Lorentzen AG, Jakobsen CJ (2016) Ultrashort acting remifentanil is not superior to long-acting sufentanil in preserving cognitive function-a randomized study. J Clin Anesth 33:127–134. doi: 10.1016/j.jclinane.2016.03.023 CrossRefPubMedGoogle Scholar
  6. 6.
    Chen L, Chen M, Du J, Wan L, Zhang L, Gu E (2016) Hyperglycemia attenuates remifentanil postconditioning-induced cardioprotection against hypoxia/reoxygenation injury in H9c2 cardiomyoblasts. J Surg Res 203(2):483–490. doi: 10.1016/j.jss.2016.03.052 CrossRefPubMedGoogle Scholar
  7. 7.
    Zuo Y, Cheng X, Gu E, Liu X, Zhang L, Cao Y (2014) Effect of aortic root infusion of sufentanil on ischemia-reperfusion injury in patients undergoing mitral valve replacement. J Cardiothorac Vasc Anesth 28(6):1474–1478. doi: 10.1053/j.jvca.2014.04.023 CrossRefPubMedGoogle Scholar
  8. 8.
    Cominacini L, Mozzini C, Garbin U, Pasini A, Stranieri C, Solani E, Vallerio P, Tinelli IA, Fratta Pasini A (2015) Endoplasmic reticulum stress and Nrf2 signaling in cardiovascular diseases. Free Radic Biol Med 88(Pt B):233–242. doi: 10.1016/j.freeradbiomed.2015.05.027 CrossRefPubMedGoogle Scholar
  9. 9.
    Yu Y, Sun G, Luo Y, Wang M, Chen R, Zhang J, Ai Q, Xing N, Sun X (2016) Cardioprotective effects of Notoginsenoside R1 against ischemia/reperfusion injuries by regulating oxidative stress- and endoplasmic reticulum stress- related signaling pathways. Sci Rep 6:21730. doi: 10.1038/srep21730 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Liao F, Zheng Y, Cai J, Fan J, Wang J, Yang J, Cui Q, Xu G, Tang C, Geng B (2015) Catestatin attenuates endoplasmic reticulum induced cell apoptosis by activation type 2 muscarinic acetylcholine receptor in cardiac ischemia/reperfusion. Sci Rep 5:16590. doi: 10.1038/srep16590 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Chen R, Kang R, Fan XG, Tang D (2014) Release and activity of histone in diseases. Cell Death Dis 5:e1370. doi: 10.1038/cddis.2014.337 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Wu D, Ingram A, Lahti JH, Mazza B, Grenet J, Kapoor A, Liu L, Kidd VJ, Tang D (2002) Apoptotic release of histones from nucleosomes. J Biol Chem 277(14):12001–12008. doi: 10.1074/jbc.M109219200 CrossRefPubMedGoogle Scholar
  13. 13.
    Barrero CA, Perez-Leal O, Aksoy M, Moncada C, Ji R, Lopez Y, Mallilankaraman K, Madesh M, Criner GJ, Kelsen SG, Merali S (2013) Histone 3.3 participates in a self-sustaining cascade of apoptosis that contributes to the progression of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 188(6):673–683. doi: 10.1164/rccm.201302-0342OC CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Zhang Z, Qin X, Tong N, Zhao X, Gong Y, Shi Y, Wu X (2012) Valproic acid-mediated neuroprotection in retinal ischemia injury via histone deacetylase inhibition and transcriptional activation. Exp Eye Res 94(1):98–108. doi: 10.1016/j.exer.2011.11.013 CrossRefPubMedGoogle Scholar
  15. 15.
    Huang H, Chen HW, Evankovich J, Yan W, Rosborough BR, Nace GW, Ding Q, Loughran P, Beer-Stolz D, Billiar TR, Esmon CT, Tsung A (2013) Histones activate the NLRP3 inflammasome in Kupffer cells during sterile inflammatory liver injury. J Immunol 191(5):2665–2679. doi: 10.4049/jimmunol.1202733 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Bosmann M, Grailer JJ, Ruemmler R, Russkamp NF, Zetoune FS, Sarma JV, Standiford TJ, Ward PA (2013) Extracellular histones are essential effectors of C5aR- and C5L2-mediated tissue damage and inflammation in acute lung injury. FASEB J 27(12):5010–5021. doi: 10.1096/fj.13-236380 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Liang DY, Li X, Clark JD (2013) Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice. J Pain 14(1):36–47. doi: 10.1016/j.jpain.2012.10.005 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Xie M, Kong Y, Tan W, May H, Battiprolu PK, Pedrozo Z, Wang ZV, Morales C, Luo X, Cho G, Jiang N, Jessen ME, Warner JJ, Lavandero S, Gillette TG, Turer AT, Hill JA (2014) Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation 129(10):1139–1151. doi: 10.1161/CIRCULATIONAHA.113.002416 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kee HJ, Kook H (2011) Roles and targets of class I and IIa histone deacetylases in cardiac hypertrophy. J Biomed Biotechnol 2011:928326. doi: 10.1155/2011/928326 CrossRefPubMedGoogle Scholar
  20. 20.
    Paillard M, Tubbs E, Thiebaut PA, Gomez L, Fauconnier J, Da Silva CC, Teixeira G, Mewton N, Belaidi E, Durand A, Abrial M, Lacampagne A, Rieusset J, Ovize M (2013) Depressing mitochondria-reticulum interactions protects cardiomyocytes from lethal hypoxia-reoxygenation injury. Circulation 128(14):1555–1565. doi: 10.1161/CIRCULATIONAHA.113.001225 CrossRefPubMedGoogle Scholar
  21. 21.
    Headrick JP, See Hoe LE, Du Toit EF, Peart JN (2015) Opioid receptors and cardioprotection—‘opioidergic conditioning’ of the heart. Br J Pharmacol 172(8):2026–2050. doi: 10.1111/bph.13042 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Sahbaie P, Liang DY, Shi XY, Sun Y, Clark JD (2016) Epigenetic regulation of spinal cord gene expression contributes to enhanced postoperative pain and analgesic tolerance subsequent to continuous opioid exposure. Mol Pain. doi: 10.1177/1744806916641950 PubMedPubMedCentralGoogle Scholar
  23. 23.
    Campos EI, Reinberg D (2009) Histones: annotating chromatin. Annu Rev Genet 43:559–599. doi: 10.1146/annurev.genet.032608.103928 CrossRefPubMedGoogle Scholar
  24. 24.
    Marinova Z, Ren M, Wendland JR, Leng Y, Liang MH, Yasuda S, Leeds P, Chuang DM (2009) Valproic acid induces functional heat-shock protein 70 via Class I histone deacetylase inhibition in cortical neurons: a potential role of Sp1 acetylation. J Neurochem 111(4):976–987. doi: 10.1111/j.1471-4159.2009.06385.x CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ren M, Leng Y, Jeong M, Leeds PR, Chuang DM (2004) Valproic acid reduces brain damage induced by transient focal cerebral ischemia in rats: potential roles of histone deacetylase inhibition and heat shock protein induction. J Neurochem 89(6):1358–1367. doi: 10.1111/j.1471-4159.2004.02406.x CrossRefPubMedGoogle Scholar
  26. 26.
    Zhao TC, Cheng G, Zhang LX, Tseng YT, Padbury JF (2007) Inhibition of histone deacetylases triggers pharmacologic preconditioning effects against myocardial ischemic injury. Cardiovasc Res 76(3):473–481. doi: 10.1016/j.cardiores.2007.08.010 CrossRefPubMedGoogle Scholar
  27. 27.
    Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, Nagata K, Harding HP, Ron D (2004) CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. Genes Dev 18(24):3066–3077. doi: 10.1101/gad.1250704 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Miyazaki Y, Kaikita K, Endo M, Horio E, Miura M, Tsujita K, Hokimoto S, Yamamuro M, Iwawaki T, Gotoh T, Ogawa H, Oike Y (2011) C/EBP homologous protein deficiency attenuates myocardial reperfusion injury by inhibiting myocardial apoptosis and inflammation. Arterioscler Thromb Vasc Biol 31(5):1124–1132. doi: 10.1161/ATVBAHA.111.224519 CrossRefPubMedGoogle Scholar
  29. 29.
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403(6765):98–103. doi: 10.1038/47513 CrossRefPubMedGoogle Scholar
  30. 30.
    Lu H, Lu L, Xu ZC, Lu YJ, Zhao B, Zhuang L, Hao BB, Zhang F (2014) Tauroursodeoxycholic acid and 4-phenyl butyric acid alleviate endoplasmic reticulum stress and improve prognosis of donation after cardiac death liver transplantation in rats. Hepatobiliary Pancreat Dis Int 13(6):586–593CrossRefPubMedGoogle Scholar
  31. 31.
    Zhang Z, Tong N, Gong Y, Qiu Q, Yin L, Lv X, Wu X (2011) Valproate protects the retina from endoplasmic reticulum stress-induced apoptosis after ischemia-reperfusion injury. Neurosci Lett 504(2):88–92. doi: 10.1016/j.neulet.2011.09.003 CrossRefPubMedGoogle Scholar
  32. 32.
    Koga T, Suico MA, Shimasaki S, Watanabe E, Kai Y, Koyama K, Omachi K, Morino-Koga S, Sato T, Shuto T, Mori K, Hino S, Nakao M, Kai H (2015) Endoplasmic reticulum (ER) stress induces sirtuin 1 (SIRT1) expression via the PI3K-Akt-GSK3beta signaling pathway and promotes hepatocellular injury. J Biol Chem 290(51):30366–30374. doi: 10.1074/jbc.M115.664169 PubMedPubMedCentralGoogle Scholar
  33. 33.
    Geiger S, Holdenrieder S, Stieber P, Hamann GF, Bruening R, Ma J, Nagel D, Seidel D (2006) Nucleosomes in serum of patients with early cerebral stroke. Cerebrovasc Dis 21(1–2):32–37. doi: 10.1159/000089591 CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Manli Chen
    • 1
    • 2
  • Qin Liu
    • 2
  • Lijian Chen
    • 2
  • Lei Zhang
    • 2
  • Erwei Gu
    • 2
    Email author
  1. 1.Department of AnesthesiologyThe First Affiliated Hospital, Medical School of Zhejiang UniversityHangzhouChina
  2. 2.Department of AnesthesiologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina

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