Protective effects of dexmedetomidine on hypoxia/reoxygenation injury in cardiomyocytes by regulating the CHOP signaling pathway

Shi,Xiaoqiao; Liu,Zhiwen; Li,Junwei

doi:10.3892/mmr.2020.11442

Protective effects of dexmedetomidine on hypoxia/reoxygenation injury in cardiomyocytes by regulating the CHOP signaling pathway

Authors:
- Xiaoqiao Shi
- Zhiwen Liu
- Junwei Li
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Affiliations: Department of Anesthesiology, The Second Affiliated Hospital of University of South China, Hengyang, Hunan 421001, P.R. China, Department of Anesthesiology, The Second Affiliated Hospital of Hunan University of Traditional Chinese Medicine, Changsha, Hunan 410005, P.R. China
Published online on: August 19, 2020 https://doi.org/10.3892/mmr.2020.11442
Pages: 3307-3315
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hypoxia/reoxygenation (H/R) injury in myocardial cells occurs frequently during cardiac surgery and affects the prognosis of patients. The present study aimed to investigate the protective effects of dexmedetomidine (Dex) on H/R injury and its association with the C/EBP‑homologous protein (CHOP) signaling pathway. An H/R model was constructed in H9C2 cells to investigate the effects of Dex on H/R injury. Cell viability, apoptosis and lactate dehydrogenase (LDH) levels were determined by MTT, flow cytometry and 2,4‑dinitrophenylhydrazine colorimetric assays, respectively. The expression levels of inflammatory factors were measured by reverse transcription‑quantitative PCR (RT‑qPCR), and CHOP and glucose‑regulated protein‑78 (Grp78) expression levels were detected by RT‑qPCR and western blotting. CHOP was overexpressed or knocked down to detect the cell viability, apoptosis, LDH level and the expression levels of inflammatory factors and Grp78. The results demonstrated that in the H/R group, cell viability was lower and apoptosis was higher, and that higher levels of LDH and inflammatory factors were present compared with those in the Dex+H/R group. Silencing of CHOP significantly reversed the H/R‑reduced cell viability, high apoptotic rate and LDH levels, as well as the elevated expression levels of inflammatory factors and Grp78 caused by H/R injury, whereas the overexpression of CHOP inhibited cell viability and promoted apoptosis, elevated LDH level and expression of inflammatory factors and Grp78 compared with the negative control. Additionally, pretreatment with Dex significantly alleviated the H/R injury; thus, Dex may protect H9C2 cells against H/R induced cell injury, possibly by suppressing the CHOP signaling pathway.

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1	Kloner RA, Shi J, Dai W, Carreno J and Zhao L: Remote ischemic conditioning in acute myocardial infarction and shock states. J Cardiovasc Pharmacol Ther. 25:3307–109. 2020. View Article : Google Scholar
2	Cooper WA, Corvera JS, Thourani VH, Puskas JD, Craver JM, Lattouf OM and Guyton RA: Perfusion-assisted direct coronary artery bypass provides early reperfusion of ischemic myocardium and facilitates complete revascularization. Ann Thorac Surg. 75:1132–1139. 2003. View Article : Google Scholar : PubMed/NCBI
3	Walker AC and Johnson NJ: Critical care of the post-cardiac arrest patient. Cardiol Clin. 36:419–428. 2018. View Article : Google Scholar : PubMed/NCBI
4	Wu D, Wang J, Li H, Xue M, Ji A and Li Y: Role of hydrogen sulfide in ischemia-reperfusion injury. Oxid Med Cell Longev. 2015:1869082015. View Article : Google Scholar : PubMed/NCBI
5	Faust KB, Chiantella V, Vinten-Johansen J and Meredith JH: Oxygen-derived free radical scavengers and skeletal muscle ischemic/reperfusion injury. Am Surg. 54:709–719. 1988.PubMed/NCBI
6	Dong HJ, Li J, Zhan H, Li Y and Su RB: Tea polyphenols promote cardiac function and energy metabolism in ex vivo rat heart with ischemic/reperfusion injury and inhibit calcium inward current in cultured rat cardiac myocytes. Nan Fang Yi Ke Da Xue Xue Bao. 36:604–608. 2016.PubMed/NCBI
7	Li JP, Guo LL, Chen Z, Wang R and Wang J: Relationship between calcium overload and myocardial ischemia reperfusion injury and intervention strategy of Chinese herbal medicine. Zhongguo Zhong Yao Za Zhi. 41:2168–2173. 2016.(In Chinese). PubMed/NCBI
8	Francis A and Baynosa R: Ischaemia-reperfusion injury and hyperbaric oxygen pathways: A review of cellular mechanisms. Diving Hyperb Med. 47:110–117. 2017.PubMed/NCBI
9	Zendedel A, Gharibi Z, Anbari K, Abbaszadeh A, Khayat ZK, Khorramabadi RM, Soleymaninejad M and Gholami M: Selenium ameliorate peripheral nerve ischemic-reperfusion injury via decreased TNF-α. Biol Trace Elem Res. 176:328–337. 2017. View Article : Google Scholar : PubMed/NCBI
10	Halladin NL: Oxidative and inflammatory biomarkers of ischemia and reperfusion injuries. Dan Med J. 62:B50542015.PubMed/NCBI
11	Laubach VE and Sharma AK: Mechanisms of lung ischemia-reperfusion injury. Curr Opin Organ Transplant. 21:246–252. 2016. View Article : Google Scholar : PubMed/NCBI
12	Li Y, Zhu X, Liu X, Du A and Yu B: miR-200a mediates protection of thymosin β-4 in cardiac microvascular endothelial cells as a novel mechanism under hypoxia-reoxygenation injury. J Cell Biochem. 120:19098–19106. 2019. View Article : Google Scholar : PubMed/NCBI
13	Gao C, Wang R, Li B, Guo Y, Yin T, Xia Y, Zhang F, Lian K, Liu Y, Wang H, et al: TXNIP/Redd1 signalling and excessive autophagy: A novel mechanism of myocardial ischaemia/reperfusion injury in mice. Cardiovasc Res. 116:645–657. 2020. View Article : Google Scholar : PubMed/NCBI
14	Manning JR, Thapa D, Zhang M, Stoner MW, Traba J, Corey C, Shiva S, Sack MN and Scott I: Loss of GCN5L1 in cardiac cells disrupts glucose metabolism and promotes cell death via reduced Akt/mTORC2 signaling. Biochem J. 476:1713–1724. 2019. View Article : Google Scholar : PubMed/NCBI
15	El Baz MM and Farahat TEM: Efficacy of adding dexmedetomidine to intra-articular levobupivacaine on postoperative pain after knee arthroscopy. Anesth Essays Res. 13:254–258. 2019. View Article : Google Scholar : PubMed/NCBI
16	Sha J, Zhang H, Zhao Y, Feng X, Hu X, Wang C, Song M and Fan H: Dexmedetomidine attenuates lipopolysaccharide-induced liver oxidative stress and cell apoptosis in rats by increasing GSK-3β/MKP-1/Nrf2 pathway activity via the α2 adrenergic receptor. Toxicol Appl Pharmacol. 364:144–152. 2019. View Article : Google Scholar : PubMed/NCBI
17	Chen L, Cao J, Cao D, Wang M, Xiang H, Yang Y, Ying T and Cong H: Protective effect of dexmedetomidine against diabetic hyperglycemia-exacerbated cerebral ischemia/reperfusion injury: An in vivo and in vitro study. Life Sci. 235:1165532019. View Article : Google Scholar : PubMed/NCBI
18	Chen N, Chen X, Xie J, Wu C and Qian J: Dexmedetomidine protects aged rats from postoperative cognitive dysfunction by alleviating hippocampal inflammation. Mol Med Rep. 20:2119–2126. 2019.PubMed/NCBI
19	Wang Q, Tan Y, Zhang N, Xu Y, Wei W, She Y, Bi X, Zhao B and Ruan X: Dexmedetomidine inhibits activation of the MAPK pathway and protects PC12 and NG108-15 cells from lidocaine-induced cytotoxicity at its maximum safe dose. Biomed Pharmacother. 91:162–166. 2017. View Article : Google Scholar : PubMed/NCBI
20	Yang CL, Tsai PS and Huang CJ: Effects of dexmedetomidine on regulating pulmonary inflammation in a rat model of ventilator-induced lung injury. Acta Anaesthesiol Taiwan. 46:151–159. 2008. View Article : Google Scholar : PubMed/NCBI
21	Jacob H, Stanisavljevic L, Storli KE, Hestetun KE, Dahl O and Myklebust MP: A four-microRNA classifier as a novel prognostic marker for tumor recurrence in stage II colon cancer. Sci Rep. 8:61572018. View Article : Google Scholar : PubMed/NCBI
22	Liu YJ, Wang DY, Yang YJ and Lei WF: Effects and mechanism of dexmedetomidine on neuronal cell injury induced by hypoxia-ischemia. BMC Anesthesiol. 17:1172017. View Article : Google Scholar : PubMed/NCBI
23	Gonzalez Villarreal C, Said Fernandez S, Soto Dominguez A, Padilla Rivas G, Garza Treviño E, Rodriguez Rocha H and Martinez Rodriguez H: Bone marrow mesenchymal stem cells: Improving transgene expression level, transfection efficiency and cell viability. J BUON. 23:1893–1903. 2018.PubMed/NCBI
24	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
25	Peng K, Qiu Y, Li J, Zhang ZC and Ji FH: Dexmedetomidine attenuates hypoxia/reoxygenation injury in primary neonatal rat cardiomyocytes. Exp Ther Med. 14:689–695. 2017. View Article : Google Scholar : PubMed/NCBI
26	Liu XR, Li T, Cao L, Yu YY, Chen LL, Fan XH, Yang BB and Tan XQ: Dexmedetomidine attenuates H2O2-induced neonatal rat cardiomyocytes apoptosis through mitochondria- and ER-medicated oxidative stress pathways. Mol Med Rep. 17:7258–7264. 2018.PubMed/NCBI
27	Jiang J, Chen DY, Liu ZT, Chen F, Zhang JJ, Cui J and Pang J: Effect of N-perfluorooctane on hypoxia/reoxygenation injury in human umbilical vein endothelial cells. Acta Cardiol Sin. 32:716–722. 2016.PubMed/NCBI
28	Chai YL, Xu JZ, Zhang YL and Sheng GT: Effects of probucol on cultured human umbilical vein endothelial cells injured by hypoxia/reoxygenation. Genet Mol Res. 15:150167522016. View Article : Google Scholar : PubMed/NCBI
29	Lin CX, Gu JL and Cao JM: The acute toxic effects of platinum nanoparticles on ion channels, transmembrane potentials of cardiomyocytes in vitro and heart rhythm in vivo in mice. Int J Nanomedicine. 14:5595–5609. 2019. View Article : Google Scholar : PubMed/NCBI
30	Fan L, Zhou W, Zhang L, Jiang D, Zhao Q and Liu L: Sitagliptin protects against hypoxia/reoxygenation (H/R)-induced cardiac microvascular endothelial cell injury. Am J Transl Res. 11:2099–2107. 2019.PubMed/NCBI
31	Kong QR, Ji DM, Li FR, Sun HY and Wang QX: MicroRNA-221 promotes myocardial apoptosis caused by myocardial ischemia-reperfusion by down-regulating PTEN. Eur Rev Med Pharmacol Sci. 23:3967–3975. 2019.PubMed/NCBI
32	Zhang Y, Zhang H, Zhang Z, Li S, Jiang W, Li X and Lv J: lncRNA MALAT1 cessation antagonizes hypoxia/reoxygenation injury in hepatocytes by inhibiting apoptosis and inflammation via the HMGB1-TLR4 axis. Mol Immunol. 112:22–29. 2019. View Article : Google Scholar : PubMed/NCBI
33	Ge L, Cai Y, Ying F, Liu H, Zhang D, He Y, Pang L, Yan D, Xu A, Ma H and Xia Z: miR-181c-5p exacerbates hypoxia/reoxygenation-induced cardiomyocyte apoptosis via targeting PTPN4. Oxid Med Cell Longev. 2019:19579202019. View Article : Google Scholar : PubMed/NCBI
34	Chen Y, Wang H, Zhang Y, Wang Z, Liu S and Cui L: Pretreatment of ghrelin protects H9c2 cells against hypoxia/reoxygenation-induced cell death via PI3K/AKT and AMPK pathways. Artif Cells Nanomed Biotechnol. 47:2179–2187. 2019. View Article : Google Scholar : PubMed/NCBI
35	Yang H, Wang C, Zhang L, Lv J and Ni H: Rutin alleviates hypoxia/reoxygenation-induced injury in myocardial cells by up-regulating SIRT1 expression. Chem Biol Interact. 297:44–49. 2019. View Article : Google Scholar : PubMed/NCBI
36	Soomro AH, Khan E, Noori S, Lone MA, Syal Z and Sheikh S: Assessment of cytokine release against oral mucosal cell line culture (TR146) stimulated by neutrophil elastase associated with Behcet's disease. Int J Dent. 2019:60956282019. View Article : Google Scholar : PubMed/NCBI
37	Zhang Q, Weng Y, Jiang Y, Zhao S, Zhou D and Xu N: Overexpression of miR-140-5p inhibits lipopolysaccharide-induced human intervertebral disc inflammation and degeneration by downregulating toll-like receptor 4. Oncol Rep. 40:793–802. 2018.PubMed/NCBI
38	Peters MC, McGrath KW, Hawkins GA, Hastie AT, Levy BD, Israel E, Phillips BR, Mauger DT, Comhair SA, Erzurum SC, et al: Plasma interleukin-6 concentrations, metabolic dysfunction, and asthma severity: A cross-sectional analysis of two cohorts. Lancet Respir Med. 4:574–584. 2016. View Article : Google Scholar : PubMed/NCBI
39	Ren J, Li C, Liu Y, Liu H and Dong Z: Protective effect of dexmedetomidine against myocardial ischemia-reperfusion injury in rabbits. Acta Cir Bras. 33:22–30. 2018. View Article : Google Scholar : PubMed/NCBI
40	Yu J, Yang W, Wang W, Wang Z, Pu Y, Chen H, Wang F and Qian J: Involvement of miR-665 in protection effect of dexmedetomidine against oxidative stress injury in myocardial cells via CB2 and CK1. Biomed Pharmacother. 115:1088942019. View Article : Google Scholar : PubMed/NCBI
41	Xu Z, Wang D, Zhou Z, Chen Q, Zhang D, Chen S, Jiang H, Jia C and Liu X: Dexmedetomidine attenuates renal and myocardial ischemia/reperfusion injury in a dose-dependent manner by inhibiting inflammatory response. Ann Clin Lab Sci. 49:31–35. 2019.PubMed/NCBI
42	Yang TR, Zhang T, Mu NH, Ruan LB, Duan JL, Zhang RP and Miao YB: Resina draconis inhibits the endoplasmic-reticulum-induced apoptosis of myocardial cells via regulating miR-423-3p/ERK signaling pathway in a tree shrew myocardial ischemia-reperfusion model. J Biosci. 44:532019. View Article : Google Scholar : PubMed/NCBI
43	Guan G, Zhang J, Liu S, Huang W, Gong Y and Gu X: Glucagon-like peptide-1 attenuates endoplasmic reticulum stress-induced apoptosis in H9c2 cardiomyocytes during hypoxia/reoxygenation through the GLP-1R/PI3K/Akt pathways. Naunyn Schmiedebergs Arch Pharmacol. 392:715–722. 2019. View Article : Google Scholar : PubMed/NCBI
44	Hu H, Tian M, Ding C and Yu S: The C/EBP homologous protein (CHOP) transcription factor functions in endoplasmic reticulum stress-induced apoptosis and microbial infection. Front Immunol. 9:30832019. View Article : Google Scholar : PubMed/NCBI
45	Zhao J, Xiang X, Zhang H, Jiang D, Liang Y, Qing W, Liu L, Zhao Q and He Z: CHOP induces apoptosis by affecting brain iron metabolism in rats with subarachnoid hemorrhage. Exp Neurol. 302:22–33. 2018. View Article : Google Scholar : PubMed/NCBI
46	Lei Y, Wang S, Ren B, Wang J, Chen J, Lu J, Zhan S, Fu Y, Huang L and Tan J: CHOP favors endoplasmic reticulum stress-induced apoptosis in hepatocellular carcinoma cells via inhibition of autophagy. PLoS One. 12:e01836802017. View Article : Google Scholar : PubMed/NCBI
47	Xu JQ, Chen B, Hu HX, Yue RC, Zhang S, Xu L, Wang H, Li Q, Tan CY, Chen HY and Zhang RY: Lycopene protects against hypoxia/reoxygenation injury in mouse cardiomyocytes by inhibiting endoplasmic reticulum stress induced apoptosis. Zhonghua Xin Xue Guan Bing Za Zhi. 44:518–523. 2016.(In Chinese). PubMed/NCBI
48	Cao L, Chen Y, Zhang Z, Li Y and Zhao P: Endoplasmic reticulum stress-induced NLRP1 inflammasome activation contributes to myocardial ischemia/reperfusion injury. Shock. 51:511–518. 2019. View Article : Google Scholar : PubMed/NCBI
49	Guan G, Yang L, Huang W, Zhang J, Zhang P, Yu H, Liu S and Gu X: Mechanism of interactions between endoplasmic reticulum stress and autophagy in hypoxia/reoxygenation-nduced injury of H9c2 cardiomyocytes. Mol Med Rep. 20:350–358. 2019.PubMed/NCBI
50	Liu C, Fu Q, Mu R, Wang F, Zhou C, Zhang L, Yu B, Zhang Y, Fang T and Tian F: Dexmedetomidine alleviates cerebral ischemia-reperfusion injury by inhibiting endoplasmic reticulum stress dependent apoptosis through the PERK-CHOP-Caspase-11 pathway. Brain Res. 1701:246–254. 2018. View Article : Google Scholar : PubMed/NCBI
51	Yang C, Gao C, Yu M, Li B, Lu Y and Lü G: Effect of dexmedetomidine pretreatment on hypoxia/reoxygenation-induced injury in human umbilical vein endothelial cells and the possible mechanism. Zhonghua Yi Xue Za Zhi. 94:3527–3530. 2014.(In Chinese). PubMed/NCBI