PEDF improves cardiac function in rats subjected to myocardial ischemia/reperfusion injury by inhibiting ROS generation via PEDF‑R

Zhao,Qixiang; Liu,Zhiwei; Huang,Bing; Yuan,Yanliang; Liu,Xiucheng; Zhang,Hu; Qiu,Fan; Zhang,Yiqian; Li,Yufeng; Miao,Haoran; Dong,Hongyan; Zhang,Zhongming

doi:10.3892/ijmm.2018.3552

PEDF improves cardiac function in rats subjected to myocardial ischemia/reperfusion injury by inhibiting ROS generation via PEDF‑R

Authors:
- Qixiang Zhao
- Zhiwei Liu
- Bing Huang
- Yanliang Yuan
- Xiucheng Liu
- Hu Zhang
- Fan Qiu
- Yiqian Zhang
- Yufeng Li
- Haoran Miao
- Hongyan Dong
- Zhongming Zhang
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Affiliations: Department of Thoracic Cardiovascular Surgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221006, P.R. China, Research Facility Center for Morphology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, P.R. China
Published online on: March 9, 2018 https://doi.org/10.3892/ijmm.2018.3552
Pages: 3243-3252
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The prevention and management of myocardial ischemia/reperfusion (MI/R) injury is an essential part of coronary heart disease surgery and is becoming a major clinical problem in the treatment of ischemic heart disease. Previous studies by our group have demonstrated that pigment epithelium‑derived factor (PEDF) improves cardiac function in rats with acute myocardial infarction and reduces hypoxia‑induced cell injury. However, the protective function and mechanisms underlying the effect of PEDF in MI/R injury remain to be fully understood. In the present study, the positive effect of PEDF in MI/R injury was confirmed by construction of the adult Sprague‑Dawley rat MI/R model. PEDF reduced myocardial infarct size and downregulated cardiomyocyte apoptosis in the I/R myocardium in this model. In addition, PEDF improved cardiac function and increased cardiac functional reserve in rats subjected to MI/R Injury. To further study the protective effect of PEDF and the underlying mechanisms in MI/R injury, a H9c2 cardiomyocyte hypoxia/reoxygenation (H/R) model was constructed. PEDF was confirmed to decrease H/R‑induced apoptosis in H9c2 cells, and this anti‑apoptotic function was abolished by pigment epithelium‑derived factor‑receptor (PEDF R) small interfering (si)RNA. Furthermore, administration of PEDF decreased the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in H/R H9c2 cells. Compared with the H/R group, PEDF decreased mitochondrial ROS, increased the mitochondrial DNA copy number, reduced xanthine oxidase and NADPH oxidase activity, as well as RAC family small GTPase 1 protein expression. However, these effects of PEDF were markedly attenuated by PEDF‑R siRNA. To the best of our knowledge, the present study is the first to identify the protective effect of PEDF in MI/R injury, and confirm that the antioxidative effect PEDF occurred via inhibition of ROS generation via PEDF‑R under MI/R conditions.

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1	Damiani G, Salvatori E, Silvestrini G, Ivanova I, Bojovic L, Iodice L and Ricciardi W: Influence of socioeconomic factors on hospital readmissions for heart failure and acute myocardial infarction in patients 65 years and older: Evidence from a systematic review. Clin Interv Aging. 10:237–245. 2015. View Article : Google Scholar : PubMed/NCBI
2	Crea F, Battipaglia I and Andreotti F: Sex differences in mechanisms, presentation and management of ischaemic heart disease. Atherosclerosis. 241:157–168. 2015. View Article : Google Scholar : PubMed/NCBI
3	Hearse DJ: Myocardial protection during ischemia and reperfusion. Mol Cell Biochem. 186:177–184. 1998. View Article : Google Scholar : PubMed/NCBI
4	Hearse DJ and Bolli R: Reperfusion induced injury: Manifestations, mechanisms, and clinical relevance. Cardiovasc Res. 26:101–108. 1992. View Article : Google Scholar : PubMed/NCBI
5	Turer AT and Hill JA: Pathogenesis of myocardial ischemia-reperfusion injury and rationale for therapy. Am J Cardiol. 106:360–368. 2010. View Article : Google Scholar : PubMed/NCBI
6	Murphy E and Steenbergen C: Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev. 88:581–609. 2008. View Article : Google Scholar : PubMed/NCBI
7	Minamino T: Cardioprotection from ischemia/reperfusion injury: Basic and translational research. Circ J. 76:1074–1082. 2012. View Article : Google Scholar : PubMed/NCBI
8	Braunersreuther V and Jaquet V: Reactive oxygen species in myocardial reperfusion injury: From physiopathology to therapeutic approaches. Curr Pharm Biotechnol. 13:97–114. 2012. View Article : Google Scholar
9	Radak Z, Zhao Z, Goto S and Koltai E: Age-associated neuro-degeneration and oxidative damage to lipids, proteins and DNA. Mol Aspects Med. 32:305–315. 2011. View Article : Google Scholar : PubMed/NCBI
10	Campos JC, Bozi LH, Bechara LR, Lima VM and Ferreira JC: Mitochondrial quality control in cardiac diseases. Front Physiol. 7:4792016. View Article : Google Scholar : PubMed/NCBI
11	Afanas'ev I: ROS and RNS signaling in heart disorders: Could antioxidant treatment be successful? Oxid Med Cell Longev. 2011:2937692011. View Article : Google Scholar : PubMed/NCBI
12	Becerra SP, Sagasti A, Spinella P and Notario V: Pigment epithelium-derived factor behaves like a noninhibitory serpin. Neurotrophic activity does not require the serpin reactive loop. J Biol Chem. 270:25992–25999. 1995. View Article : Google Scholar : PubMed/NCBI
13	Rychli K, Kaun C, Hohensinner PJ, Dorfner AJ, Pfaffenberger S, Niessner A, Bauer M, Dietl W, Podesser BK, Maurer G, et al: The anti-angiogenic factor PEDF is present in the human heart and is regulated by anoxia in cardiac myocytes and fibroblasts. J Cell Mol Med. 14:198–205. 2010. View Article : Google Scholar :
14	Gao X, Zhang H, Zhuang W, Yuan G, Sun T, Jiang X, Zhou Z, Yuan H, Zhang Z and Dong H: PEDF and PEDF-derived peptide 44mer protect cardiomyocytes against hypoxia-induced apoptosis and necroptosis via anti-oxidative effect. Sci Rep. 4:56372014. View Article : Google Scholar : PubMed/NCBI
15	Zhang H, Sun T, Jiang X, Yu H, Wang M, Wei T, Cui H, Zhuang W, Liu Z, Zhang Z and Dong H: PEDF and PEDF-derived peptide 44mer stimulate cardiac triglyceride degradation via ATGL. J Transl Med. 13:682015. View Article : Google Scholar : PubMed/NCBI
16	Zhang H, Wang Z, Feng SJ, Xu L, Shi HX, Chen LL, Yuan GD, Yan W, Zhuang W, Zhang YQ, et al: PEDF improves cardiac function in rats with acute myocardial infarction via inhibiting vascular permeability and cardiomyocyte apoptosis. Int J Mol Sci. 16:5618–5634. 2015. View Article : Google Scholar : PubMed/NCBI
17	Notari L, Baladron V, Aroca-Aguilar JD, Balko N, Heredia R, Meyer C, Notario PM, Saravanamuthu S, Nueda ML, Sanchez-Sanchez F, et al: Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem. 281:38022–38037. 2006. View Article : Google Scholar : PubMed/NCBI
18	Bernard A, Gao-Li J, Franco CA, Bouceba T, Huet A and Li Z: Laminin receptor involvement in the anti-angiogenic activity of pigment epithelium-derived factor. J Biol Chem. 284:10480–10490. 2009. View Article : Google Scholar : PubMed/NCBI
19	Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A and Zechner R: Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science. 306:1383–1386. 2004. View Article : Google Scholar : PubMed/NCBI
20	Hirsch J, Johnson CL, Nelius T, Kennedy R, Riese Wd and Filleur S: PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ. Cytokine. 55:202–210. 2011. View Article : Google Scholar : PubMed/NCBI
21	Wang XY, Zhang YQ, Lu P, Zhang H, Li Y, Dong H and Zhang Z: PEDF attenuates hypoxia-induced apoptosis and necrosis in H9c2 cells by inhibiting p53 mitochondrial translocation via PEDF-R. Biochem Biophys Res Commun. 465:394–401. 2015. View Article : Google Scholar : PubMed/NCBI
22	Lu P, Zhang YQ, Zhang H, Li YF, Wang XY, Xu H, Liu ZW, Li L, Dong HY and Zhang ZM: Pigment epithelium-derived factor (PEDF) improves ischemic cardiac functional reserve through decreasing hypoxic cardiomyocyte contractility through PEDF receptor (PEDF-R). J Am Heart Assoc. 5:e0031792016. View Article : Google Scholar : PubMed/NCBI
23	Reim DF and Speicher DW: N-terminal sequence analysis of proteins and peptides. Curr Protoc Protein Sci. Chapter 11: Unit 11.10. 2001.
24	Chen L, Zhao X, Liang G, Sun J, Lin Z, Hu R, Chen P, Zhang Z, Zhou L and Li Y: Recombinant SFRP5 protein significantly alleviated intrahepatic inflammation of nonalcoholic steatohepatitis. Nutr Metab (Lond). 14:562017. View Article : Google Scholar
25	National Research Council: Guide for the Care and Use of Laboratory Animals. 8th edition. The National Academies Press; Washington, DC: 2011
26	European Commission: Directive 2010/63/EU of the European Parliament and of the council of 22 September 2010 on the protection of animals used for scientific purposes. Off J Eur Union. L276:33–79. 2010.
27	Zhang Y, Li Y, Wang X, Zhao Q, Lu P, Zhang H, Dong H and Zhang Z: A closed-chest rat model of myocardial isch-aemia/reperfusion supports direct intramyocardial gene delivery. Exp Ther Med. In press.
28	Black SC and Rodger IW: Methods for studying experimental myocardial ischemic and reperfusion injury. J Pharmacol Toxicol Methods. 35:179–190. 1996. View Article : Google Scholar : PubMed/NCBI
29	Peshavariya HM, Dusting GJ and Selemidis S: Analysis of dihydroethidium fluorescence for the detection of intracellular and extracellular superoxide produced by NADPH oxidase. Free Radic Res. 41:699–712. 2007. View Article : Google Scholar : PubMed/NCBI
30	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
31	Tsutsui H, Kinugawa S and Matsushima S: Oxidative stress and mitochondrial DNA damage in heart failure. Circ J. 72(Suppl A): A31–A37. 2008. View Article : Google Scholar : PubMed/NCBI
32	Li JM, Zhu HQ, Shen E, Wan L, Arnold JMO and Peng TQ: Deficiency of Rac1 blocks NADPH oxidase activation, inhibits endoplasmic reticulum stress, and reduces myocardial remodeling in a mouse model of type 1 diabetes. Diabetes. 59:2033–2042. 2010. View Article : Google Scholar : PubMed/NCBI
33	Garcia-Dorado D, Andres-Villarreal M, Ruiz-Meana M, Inserte J and Barba I: Myocardial edema: A translational view. J Mol Cell Cardiol. 52:931–939. 2012. View Article : Google Scholar : PubMed/NCBI
34	Gustafsson AB and Gottlieb RA: Heart mitochondria: Gates of life and death. Cardiovasc Res. 77:334–343. 2008. View Article : Google Scholar
35	Zorov DB, Filburn CR, Klotz LO, Zweier JL and Sollott SJ: Reactive oxygen species (ROS)-induced ROS release: A new phenomenon accompanying induction of the mitochondrial permeability transition in cardiac myocytes. J Exp Med 1. 92:1001–1014. 2000. View Article : Google Scholar
36	Zhou ZX, Wang Z, Guan QH, Qiu F, Li Y, Liu Z, Zhang H, Dong H and Zhang Z: PEDF inhibits the activation of NLRP3 inflammasome in hypoxia cardiomyocytes through PEDF receptor/phospholipase A2. Int J Mol Sci. 17:E20642016. View Article : Google Scholar : PubMed/NCBI
37	Kuo HF, Liu PL, Chong IW, Liu YP, Chen YH, Ku PM, Li CY, Chen HH, Chiang HC, Wang CL, et al: Pigment epithelium-derived factor mediates autophagy and apoptosis in myocardial hypoxia/reoxygenation injury. PLoS One. 11:e01560592016. View Article : Google Scholar : PubMed/NCBI