Protection of rat liver against hepatic ischemia-reperfusion injury by a novel selenocysteine-containing 7-mer peptide

Jiang,Qianqian; Pan,Yu; Cheng,Yupeng; Li,Huiling; Li,Hui

doi:10.3892/mmr.2016.5464

Protection of rat liver against hepatic ischemia-reperfusion injury by a novel selenocysteine-containing 7-mer peptide

Authors:
- Qianqian Jiang
- Yu Pan
- Yupeng Cheng
- Huiling Li
- Hui Li
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Affiliations: Pharmaceutical College, Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang 150040, P.R. China, School of Environment and Chemical Engineering, Heilongjiang University of Science and Technology, Harbin, Heilongjiang 150022, P.R. China, Department of Biochemistry and Molecular Biology, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: July 1, 2016 https://doi.org/10.3892/mmr.2016.5464
Pages: 2007-2015
Copyright: © Jiang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Hepatic ischemia-reperfusion (I-R) injury causes acute organ damage or dysfunction, and remains a problem for liver transplantation. In the I-R phase, the generation of reactive oxygen species aggravates the injury. In the current study, a novel selenocysteine-containing 7‑mer peptide (H-Arg-Sec-Gly-Arg-Asn-Ala-Gln-OH) was constructed to imitate the active site of an antioxidant enzyme, glutathione peroxidase (GPX). The 7‑mer peptide which has a lower molecular weight, and improved water‑solubility, higher stability and improved cell membrane permeability compared with other GPX mimics. Its GPX activity reached 13 U/µmol, which was 13 times that of ebselen (a representative GPX mimic). The effect of this GPX mimic on I‑R injury of the liver was assessed in rats. The 7‑mer peptide significantly inhibited the increase in serum hepatic amino‑transferases, tissue malondialdehyde, nitric oxide contents, myeloperoxidase activity and decrease of GPX activity compared with I‑R tissue. Following treatment with the 7‑mer peptide, the expression of B‑cell CLL/lymphoma‑2 (Bcl‑2) was significantly upregulated at the mRNA and protein level compared with the I‑R group, as determined by reverse transcription‑polymerase chain reaction and immunohistochemistry, respectively. By contrast, Bcl‑2 associated X protein (Bax) was downregulated by the 7‑mer peptide compared the I‑R group. Histological and ultrastructural changes of the rat liver tissue were also compared among the experimental groups. The results of the current study suggest that the 7‑mer peptide protected the liver against hepatic I‑R injury via suppression of oxygen‑derived free radicals and regulation of Bcl‑2 and Bax expression, which are involved in the apoptosis of liver cells. The findings of the present study will further the investigation of the 7-mer peptide as an effective therapeutic agent in hepatic I-R injury.

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1	Eltzschig HK and Eckle T: Ischemia and reperfusion-from mechanism to translation. Nat Med. 17:1391–1401. 2011. View Article : Google Scholar : PubMed/NCBI
2	Klune JR and Tsung A: Molecular biology of liver ischemia/reperfusion injury: Established mechanisms and recent advancements. Surg Clin North Am. 90:665–677. 2010. View Article : Google Scholar : PubMed/NCBI
3	Taki-Eldin A, Zhou L, Xie HY, Chen KJ, Yu D, He Y and Zheng SS: Triiodothyronine attenuates hepatic ischemia/reperfusion injury in a partial hepatectomy model through inhibition of proinflammatory cytokines, transcription factors, and adhesion molecules. J Surg Res. 178:646–656. 2012. View Article : Google Scholar : PubMed/NCBI
4	Katsumi H, Nishikawa M, Yamashita F and Hashida M: Prevention of hepatic ischemia/reperfusion injury by prolonged delivery of nitric oxide to the circulating blood in mice. Transplantation. 85:264–269. 2008. View Article : Google Scholar : PubMed/NCBI
5	Katsumi H, Nishikawa M, Yasui H, Yamashita F and Hashida M: Prevention of ischemia/reperfusion injury by hepatic targeting of nitric oxide in mice. J Control Release. 140:12–17. 2009. View Article : Google Scholar : PubMed/NCBI
6	Chan PH: Role of oxidants in ischemic brain damage. Stroke. 27:1124–1129. 1996. View Article : Google Scholar : PubMed/NCBI
7	Mizoe A, Kondo S, Azuma T, Fujioka H, Tanaka K, Hashida M and Kanematsu T: Preventive effects of superoxide dismutase derivatives modified with monosaccharides on reperfusion injury in rat liver transplantation. J Surg Res. 73:160–165. 1997. View Article : Google Scholar
8	Kusumoto K, Morimoto T, Minor T, Uchino J and Isselhard W: Allopurinol effects in rat liver transplantation on recovery of energy metabolism and free radical-induced damage. Eur Surg Res. 27:285–291. 1995. View Article : Google Scholar : PubMed/NCBI
9	Koeppel TA, Lehmann TG, Thies JC, Gehrcke R, Gebhard MM, Herfarth C, Otto G and Post S: Impact of N-acetylcysteine on the hepatic microcirculation after orthotopic liver transplantation. Transplantation. 61:1397–1402. 1996. View Article : Google Scholar : PubMed/NCBI
10	Lubos E, Loscalzo J and Handy DE: Glutathione peroxidase-1 in health and disease: From molecular mechanisms to therapeutic opportunities. Antioxid Redox Signal. 15:1957–1997. 2011. View Article : Google Scholar :
11	Sies H: Ebselen, a selenoorganic compound as glutathione peroxidase mimic. Free Radic Bio Med. 14:313–323. 1993. View Article : Google Scholar
12	Epp O, Landensteine R and Wendel A: The refined structure of the selenoenzyme glutathione peroxidase at 0.2-nm resolution. Eur J Biochem. 133:51–69. 1983. View Article : Google Scholar : PubMed/NCBI
13	Kohmoto J, Nakao A, Stolz DB, Kaizu T, Tsung A, Ikeda A, Shimizu H, Takahashi T, Tomiyama K, Sugimoto R, et al: Carbon monoxide protects rat lung transplants from ischemia-reperfusion injury via a mechanism involving p38 MAPK pathway. Am J Transplant. 7:2279–2290. 2007. View Article : Google Scholar : PubMed/NCBI
14	Gavish M, Zakut R, Wilckek M and Givol D: Preparation of a semisynthetic antibody. Biochemistry. 17:1345–1351. 1978. View Article : Google Scholar : PubMed/NCBI
15	Santos AA, Braga-Neto MB, Oliveira MR, Freire RS, Barros EB, Santiago TM, Rebelo LM, Mermelstein C, Warren CA, Guerrant RL and Brito GA: Glutamine and alanyl-glutamine increase RhoA expression and reduce Clostridium difficile toxin-a-induced intestinal epithelial cell damage. Biomed Res Int. 2013:1520522013. View Article : Google Scholar : PubMed/NCBI
16	Jia CJ, Dai CL, Zhang X, Cui K, Xu F and Xu YQ: Alanyl-glutamine dipeptide inhibits hepatic ischemia-reperfusion injury in rats. World J Gastroenterol. 12:1373–1378. 2006. View Article : Google Scholar : PubMed/NCBI
17	Braga-Neto MB, Oliveira BM, Rodrigues RS, Noronha FJ, Leitao RF, Brito GA, Lima AA, Guerrant RL and Warren CA: Protective effects of alanyl-glutamine supplementation against nelfinavir-induced epithelial impairment in IEC-6 cells and in mouse intestinal mucosa. Cancer Biol Ther. 13:1482–1490. 2012. View Article : Google Scholar : PubMed/NCBI
18	Dobashi K, Ghosh B, Orak JK, Singh I and Singh AK: Kidney ischemia-reperfusion: Modulation of antioxidant defenses. Mol Cell Biochem. 205:1–11. 2000. View Article : Google Scholar : PubMed/NCBI
19	Kim HJ, Joe Y, Kong JS, Jeong SO, Cho GJ, Ryter SW and Chung HT: Carbon monoxide protects against hepatic ischemia/reperfusion injury via ROS-dependent Akt signaling and inhibition of glycogen synthase kinase 3ß. Oxid Med Cell Longev. 2013:3064212013. View Article : Google Scholar
20	Pan S, Liu L, Pan H, Ma Y, Wang D, Kang K, Wang J, Sun B, Sun X and Jiang H: Protective effects of hydroxytyrosol on liver ischemia/reperfusion injury in mice. Mol Nutr Food Res. 57:1218–1227. 2013. View Article : Google Scholar : PubMed/NCBI
21	Connor HD, Gao W, Nukina S, Lemasters JJ, Mason RP and Thurman RG: Evidence that free radicals are involved in graft failure following orthotopic liver transplantation in the rat-an electron paramagnetic resonance spin trapping study. Transplantation. 54:199–204. 1992. View Article : Google Scholar : PubMed/NCBI
22	Burke A, FitzGerald GA and Lucey MR: A prospective analysis of oxidative stress and liver transplantation. Transplantation. 74:217–221. 2002. View Article : Google Scholar : PubMed/NCBI
23	Wang XL, Liu HR, Tao L, Liang F, Yan L, Zhao RR, Lopez BL, Christopher TA and Ma XL: Role of iNOS-derived reactive nitrogen species and resultant nitrative stress in leukocytes-induced cardiomyocyte apoptosis after myocardial ischemia/reperfusion. Apoptosis. 12:1209–1217. 2007. View Article : Google Scholar : PubMed/NCBI
24	de Vries DK, Kortekaas KA, Tsikas D, Wijermars LG, van Noorden CJ, Suchy MT, Cobbaert CM, Klautz RJ, Schaapherder AF and Lindeman JH: Oxidative damage in clinical ischemia/reperfusion injury: A reappraisal. Antioxid Redox Signal. 19:535–545. 2013. View Article : Google Scholar : PubMed/NCBI
25	Simonsen U, Rodriguez-Rodriguez R, Dalsgaard T, Buus NH and Stankevicius E: Novel approaches to improving endothelium-dependent nitric oxide-mediated vasodilatation. Pharmacol Rep. 61:105–115. 2009. View Article : Google Scholar : PubMed/NCBI
26	Sheng M, Zhou Y, Yu W, Weng Y, Xu R and Du H: Protective effect of Berberine pretreatment in hepatic ischemia/reperfusion injury of rat. Transplant Proc. 47:275–282. 2015. View Article : Google Scholar : PubMed/NCBI
27	Wang C, Chen K, Xia Y, Dai W, Wang F, Shen M, Cheng P, Wang J, Lu J, Zhang Y, et al: N-acetylcysteine attenuates ischemia-reperfusion-induced apoptosis and autophagy in mouse liver via regulation of the ROS/JNK/Bcl-2 pathway. PLoS One. 9:e1088552014. View Article : Google Scholar : PubMed/NCBI
28	Zhao J, Ming Y, Wan Q, Ye S, Xie S, Zhu Y, Wang Y, Zhong Z, Li L and Ye Q: Gypenoside attenuates hepatic ischemia/reperfusion injury in mice via anti-oxidative and anti-apoptotic bioactivities. Exp Ther Med. 7:1388–1392. 2014.PubMed/NCBI
29	Oltvai ZN, Milliman CL and Korsmeyer SJ: Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 74:609–619. 1993. View Article : Google Scholar : PubMed/NCBI
30	Bartling B, Holtz J and Darmer D: Contribution of myocyte apoptosis to myocardial infarction? Basic Res Cardiol. 93:71–84. 1998. View Article : Google Scholar : PubMed/NCBI
31	Jin S and Dai CL: Attenuation of reperfusion-induced hepatocyte apoptosis in associated with reversed bcl-2/bax ratio in hemi-hepatic artery-preserved portal occlusion. J Surg Res. 174:298–304. 2012. View Article : Google Scholar