Remifentanil postconditioning ameliorates histone H3 acetylation modification in H9c2 cardiomyoblasts after hypoxia/reoxygenation via attenuating endoplasmic reticulum stress
- 444 Downloads
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.
KeywordsCardioprotection Remifentanil postconditioning Endoplasmic reticulum stress Histone 3 HDAC3 Apoptosis
We thank LetPub (http://www.letpub.com) for its linguistic assistance during the preparation of this manuscript.
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).
- 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
- 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.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
- 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
- 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.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
- 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
- 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
- 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.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
- 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
- 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
- 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