Exogenous hydrogen sulfide protects against hepatic ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress and cell apoptosis

Chen,Liang; Ma,Keqiang; Fan,Haining; Wang,Xiaolong; Cao,Tiansheng

doi:10.3892/etm.2021.10231

Exogenous hydrogen sulfide protects against hepatic ischemia/reperfusion injury by inhibiting endoplasmic reticulum stress and cell apoptosis

Authors:
- Liang Chen
- Keqiang Ma
- Haining Fan
- Xiaolong Wang
- Tiansheng Cao
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Affiliations: Department of General Surgery, Affiliated Huadu Hospital of Southern Medical University (People's Hospital of Huadu District), Guangzhou, Guangdong 510800, P.R. China, Department of Hepatopancreatobiliary Surgery, the Affiliated Hospital of Qinghai University, Xining, Qinghai 810001, P.R. China
Published online on: May 25, 2021 https://doi.org/10.3892/etm.2021.10231
Article Number: 799
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The aim of the present study was to explore the effect of exogenous hydrogen sulphide (H2S) on endoplasmic reticulum (ER) stress (ERS) in a rat model of hepatic ischemia/reperfusion (I/R) injury. A total of 48 Sprague‑Dawley rats were randomly divided into four groups (n=12/group) as follows: Sham, I/R, I/R preceded by NaHS (I/R‑NaHS) and I/R preceded by L‑C‑propargylglycine (PAG), a H₂S inhibitor (I/R‑PAG). With the exception of the sham group, the rats in the other groups were subjected to 30 min hepatic warm ischemia followed by reperfusion for 6 or 12 h. Hepatic function was evaluated by serum concentrations of alanine aminotransferase (ALT). Apoptosis of hepatic cells was assessed by TUNEL staining and measurement of caspase‑12 expression. The expression levels of ERS‑associated proteins and mRNAs of pancreatic ER eukaryotic translation initiation factor‑2a kinase (PERK), activating transcription factor‑6 (ATF6), glucose‑regulated protein (GRP) 78, TNF‑receptor‑associated factor (TRAF)‑2, C/EBP homologous protein (CHOP) and caspase‑12 were also measured by western blotting and reverse transcription‑quantitative PCR. The serum concentrations of ALT in the I/R and I/R‑PAG groups were found to be significantly higher compared with those in the sham and I/R‑NaHS groups after 6 h of reperfusion; in addition, the ALT level returned to normal in the I/R group, while it increased further in the I/R‑PAG group after 12 h of reperfusion. A higher cell apoptosis rate was observed in the I/R and I/R‑PAG groups and the highest cell apoptosis rate was observed in the I/R‑PAG group; correspondingly, the expression of caspase‑12 was increased in the I/R and I/R‑PAG groups. H2S appeared to significantly attenuate hepatic I/R‑induced ERS response, as indicated by the decreased expression of ATF6, PERK, GRP78, TRAF2 and CHOP. Endogenous H₂S may serve a hepatoprotective function after I/R, and inhibition of endogenous H2S results in aggravation of I/R damage. Exogenous H₂S was shown to inhibit ERS‑related gene expression, leading to suppression of inflammatory reaction and improvement of I/R damage. Therefore, exogenous H₂S has therapeutic potential to alleviate hepatic I/R injury.

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1	Jaeschke H and Woolbright BL: Current strategies to minimize hepatic ischemia-reperfusion injury by targeting reactive oxygen species. Transplant Rev (Orlando). 26:103–114. 2012.PubMed/NCBI View Article : Google Scholar
2	Hines IN and Grisham MB: Divergent roles of superoxide and nitric oxide in liver ischemia and reperfusion injury. J Clin Biochem Nutr. 48:50–56. 2011.PubMed/NCBI View Article : Google Scholar
3	Kupiec-Weglinski JW and Busuttil RW: Ischemia and reperfusion injury in liver transplantation. Transplant Proc. 37:1653–1656. 2005.PubMed/NCBI View Article : Google Scholar
4	Urakami H, Abe Y and Grisham MB: Role of reactive metabolites of oxygen and nitrogen in partial liver transplantation: Lessons learned from reduced-size liver ischaemia and reperfusion injury. Clin Exp Pharmacol Physiol. 34:912–919. 2007.PubMed/NCBI View Article : Google Scholar
5	Abu-Amara M, Yang SY, Tapuria N, Fuller B, Davidson B and Seifalian A: Liver ischemia/reperfusion injury: Processes in inflammatory networks--a review. Liver Transpl. 16:1016–1032. 2010.PubMed/NCBI View Article : Google Scholar
6	Duvigneau JC, Kozlov AV, Zifko C, Postl A, Hartl RT, Miller I, Gille L, Staniek K, Moldzio R, Gregor W, et al: Reperfusion does not induce oxidative stress but sustained endoplasmic reticulum stress in livers of rats subjected to traumatic-hemorrhagic shock. Shock. 33:289–298. 2010.PubMed/NCBI View Article : Google Scholar
7	Deng Y, Srivastava R and Howell SH: Endoplasmic reticulum (ER) stress response and its physiological roles in plants. Int J Mol Sci. 14:8188–8212. 2013.PubMed/NCBI View Article : Google Scholar
8	Xu C, Bailly-Maitre B and Reed JC: Endoplasmic reticulum stress: Cell life and death decisions. J Clin Invest. 115:2656–2664. 2005.PubMed/NCBI View Article : Google Scholar
9	Emadali A, Nguyên DT, Rochon C, Tzimas GN, Metrakos PP and Chevet E: Distinct endoplasmic reticulum stress responses are triggered during human liver transplantation. J Pathol. 207:111–118. 2005.PubMed/NCBI View Article : Google Scholar
10	Wang R: Physiological implications of hydrogen sulfide: A whiff exploration that blossomed. Physiol Rev. 92:791–896. 2012.PubMed/NCBI View Article : Google Scholar
11	Kimura H: Hydrogen sulfide: From brain to gut. Antioxid Redox Signal. 12:1111–1123. 2010.PubMed/NCBI View Article : Google Scholar
12	Calvert JW, Coetzee WA and Lefer DJ: Novel insights into hydrogen sulfide--mediated cytoprotection. Antioxid Redox Signal. 12:1203–1217. 2010.PubMed/NCBI View Article : Google Scholar
13	Kabil O and Banerjee R: Redox biochemistry of hydrogen sulfide. J Biol Chem. 285:21903–21907. 2010.PubMed/NCBI View Article : Google Scholar
14	Jha S, Calvert JW, Duranski MR, Ramachandran A and Lefer DJ: Hydrogen sulfide attenuates hepatic ischemia-reperfusion injury: Role of antioxidant and antiapoptotic signaling. Am J Physiol Heart Circ Physiol. 295:H801–H806. 2008.PubMed/NCBI View Article : Google Scholar
15	Tan EK, Shuh M, Francois-Vaughan H, Sanders JA and Cohen AJ: Negligible oval cell proliferation following ischemia-reperfusion injury with and without partial hepatectomy. Ochsner J. 17:31–37. 2017.PubMed/NCBI
16	Zhang T, Ma Y, Xu KQ and Huang WQ: Pretreatment of parecoxib attenuates hepatic ischemia/reperfusion injury in rats. BMC Anesthesiol. 15(165)2015.PubMed/NCBI View Article : Google Scholar
17	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.PubMed/NCBI View Article : Google Scholar
18	Wei H, Zhang R, Jin H, Liu D, Tang X, Tang C and Du J: Hydrogen sulfide attenuates hyperhomocysteinemia-induced cardiomyocytic endoplasmic reticulum stress in rats. Antioxid Redox Signal. 12:1079–1091. 2010.PubMed/NCBI View Article : Google Scholar
19	Georgiev P, Dahm F, Graf R and Clavien PA: Blocking the path to death: Anti-apoptotic molecules in ischemia/reperfusion injury of the liver. Curr Pharm Des. 12:2911–2921. 2006.PubMed/NCBI View Article : Google Scholar
20	Jaeschke H and Lemasters JJ: Apoptosis versus oncotic necrosis in hepatic ischemia/reperfusion injury. Gastroenterology. 125:1246–1257. 2003.PubMed/NCBI View Article : Google Scholar
21	Shore GC, Papa FR and Oakes SA: Signaling cell death from the endoplasmic reticulum stress response. Curr Opin Cell Biol. 23:143–149. 2011.PubMed/NCBI View Article : Google Scholar
22	Lee AS: The glucose-regulated proteins: Stress induction and clinical applications. Trends Biochem Sci. 26:504–510. 2001.PubMed/NCBI View Article : Google Scholar
23	Szegezdi E, Logue SE, Gorman AM and Samali A: Mediators of endoplasmic reticulum stress-induced apoptosis. EMBO Rep. 7:880–885. 2006.PubMed/NCBI View Article : Google Scholar
24	Tabas I and Ron D: Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress. Nat Cell Biol. 13:184–190. 2011.PubMed/NCBI View Article : Google Scholar
25	Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA and Yuan J: Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature. 403:98–103. 2000.PubMed/NCBI View Article : Google Scholar
26	Szegezdi E, Fitzgerald U and Samali A: Caspase-12 and ER-stress-mediated apoptosis: The story so far. Ann N Y Acad Sci. 1010:186–194. 2003.PubMed/NCBI View Article : Google Scholar
27	Obert DP, Wolpert AK and Korff S: Modulation of endoplasmic reticulum stress influences ischemia-reperfusion injury after hemorrhagic shock. Shock. 52:e76–e84. 2019.PubMed/NCBI View Article : Google Scholar
28	Emerson B, Dransfield I, Morton NM and Gray GA: Expression and localisation of H₂S metabolising enzymes in the murine myocardium and liver. Nitric Oxide. 27:S29–S30. 2012.
29	Han SJ, Kim JI, Park JW and Park KM: Hydrogen sulfide accelerates the recovery of kidney tubules after renal ischemia/reperfusion injury. Nephrol Dial Transplant. 30:1497–1506. 2015.PubMed/NCBI View Article : Google Scholar