(Pro)renin receptor (PRR) contributes to regulating many physiological and pathological processes; however, the role of PRR-mediated signaling pathways in myocardial ischemia/reperfusion injury (IRI) remains unclear. In this study, we used an in vitro model of hypoxia/reoxygenation (H/R) to mimic IRI and carried out PRR knockdown by siRNA and PRR overexpression using cDNA in H9c2 cells. Cell proliferation activity was examined by MTT and Cell Counting Kit-8 (CCK-8) assays. Apoptosis-related factors, autophagy markers and beta-catenin pathway activity were assessed by real-time PCR and western blotting. After 24 h of hypoxia followed by 2 h of reoxygenation, the expression levels of PRR, LC3B-I/II, Beclin1, cleaved caspase-3, cleaved caspase-9 and Bax were upregulated, suggesting that apoptosis and autophagy were increased in H9c2 cells. Contrary to the effects of PRR downregulation, the overexpression of PRR inhibited proliferation, induced apoptosis, increased the expression of pro-apoptotic factors and autophagy markers, and promoted activation of the beta-catenin pathway. Furthermore, all these effects were reversed by treatment with the beta-catenin antagonist DKK-1. Thus, we concluded that PRR activation can trigger H/R-induced apoptosis and autophagy in H9c2 cells through the beta-catenin signaling pathway, which may provide new therapeutic targets for the prevention and treatment of myocardial IRI.

Department of Cardiology The 1st Affiliated Hospital of Dalian Medical University Dalian Liaoning People's Republic of China

Zobrazit více v PubMed

BARANDON L, COUFFINHAL T, EZAN J, DUFOURCQ P, COSTET P, ALZIEU P, LEROUX L, MOREAU C, DARE D, DUPLAA C. Reduction of infarct size and prevention of cardiac rupture in transgenic mice overexpressing FrzA. Circulation. 2003;108:2282–2289. doi: 10.1161/01.cir.0000093186.22847.4c. PubMed DOI

BENJAMIN EJ, BLAHA MJ, CHIUVE SE, CUSHMAN M, DAS SR, DEO R, De FERRANTI SD, FLOYD J, FORNAGE M, GILLESPIE C, ISASI CR, JIMENEZ MC, JORDAN LC, JUDD SE, LACKLAND D, LICHTMAN JH, LISABETH L, LIU S, LONGENECKER CT, MACKEY RH, et al. Heart Disease and Stroke Statistics-2017 Update: A Report From the American Heart Association. Circulation. 2017;135:e146–e603. doi: 10.1161/cir.0000000000000485. PubMed DOI PMC

BINGER KJ, MULLER DN. Autophagy and the (Pro)renin receptor. Front Endocrinol (Lausanne) 2013;4:155. doi: 10.3389/fendo.2013.00155. PubMed DOI PMC

CRUCIAT CM, OHKAWARA B, ACEBRON SP, KARAULANOV E, REINHARD C, INGELFINGER D, BOUTROS M, NIEHRS C. Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science. 2010;327:459–463. doi: 10.1126/science.1179802. PubMed DOI

DING VW, CHEN RH, McCORMICK F. Differential regulation of glycogen synthase kinase 3beta by insulin and Wnt signaling. J Biol Chem. 2000;275:32475–32481. doi: 10.1074/jbc.m005342200. PubMed DOI

DOGAN R, FARSAK B, ISBIR S, SARIGUL A, TUNCER M, KILINC K. Protective effect of lisinopril against ischemia-reperfusion injury in isolated guinea pig hearts. J Cardiovasc Surg (Torino) 2001;42:43–48. doi: 10.1080/00365519850186698. PubMed DOI

ELLMERS LJ, RADEMAKER MT, CHARLES CJ, YANDLE TG, RICHARDS AM. (Pro)renin receptor blockade ameliorates cardiac injury and remodeling and improves function after myocardial infarction. J Card Fail. 2016;22:64–72. doi: 10.1016/j.cardfail.2015.08.341. PubMed DOI

FORDE JE, DALE TC. Glycogen synthase kinase 3: a key regulator of cellular fate. Cell Mol Life Sci. 2007;64:1930–1944. doi: 10.1007/s00018-007-7045-7. PubMed DOI PMC

FUKUMOTO S, HSIEH CM, MAEMURA K, LAYNE MD, YET SF, LEE KH, MATSUI T, ROSENZWEIG A, TAYLOR WG, RUBIN JS, PERRELLA MA, LEE ME. Akt participation in the Wnt signaling pathway through Dishevelled. J Biol Chem. 2001;276:17479–17483. doi: 10.1074/jbc.c000880200. PubMed DOI

GRANADO M, FERNÁNDEZ N, MONGE L, CARRENO-TARRAGONA G, FIGUERAS JC, AMOR S, GARCIA-VILLALON AL. Long-term effects of early overnutrition in the heart of male adult rats: role of the renin-angiotensin system. PLoS One. 2014;8:e65172. doi: 10.1371/journal.pone.0065172. PubMed DOI PMC

HAMADA K, TANIGUCHI Y, SHIMAMURA Y, INOUE K, OGATA K, ISHIHARA M, HORINO T, FUJIMOTO S, OHGURO T, YOSHIMOTO Y, IKEBE M, YUASA K, HOSHINO E, IIYAMA T, ICHIHARA A, TERADA Y. Serum level of soluble (pro)renin receptor is modulated in chronic kidney disease. Clin Exp Nephrol. 2013;17:848–856. doi: 10.1007/s10157-013-0803-y. PubMed DOI

HOU S, TIAN T, QI D, SUN K, YUAN Q, WANG Z, QIN Z, WU Z, CHEN Z, ZHANG J. S100A4 promotes lung tumor development through beta-catenin pathway-mediated autophagy inhibition. Cell Death Dis. 2018;9:277. doi: 10.1038/s41419-018-0319-1. PubMed DOI PMC

HU P, KE C, GUO X, REN P, TONG Y, LUO S, HE Y, WEI Z, CHENG B, LI R, LUO J, MENG Z. Both glypican-3/Wnt/beta-catenin signaling pathway and autophagy contributed to the inhibitory effect of curcumin on hepatocellular carcinoma. Dig Liver Dis. 2019;51:120–126. doi: 10.1016/j.dld.2018.06.012. PubMed DOI

IBANEZ B, HEUSCH G, OVIZE M, Van de WERF F. Evolving therapies for myocardial ischemia/reperfusion injury. J Am Coll Cardiol. 2015;65:1454–1471. doi: 10.1016/j.jacc.2015.02.032. PubMed DOI

JUHASZOVA M, ZOROV DB, KIM SH, PEPE S, FU Q, FISHBEIN KW, ZIMAN BD, WANG S, YTREHUS K, ANTOS CL, OLSON EN, SOLLOTT SJ. Glycogen synthase kinase-3beta mediates convergence of protection signaling to inhibit the mitochondrial permeability transition pore. J Clin Invest. 2004;113:1535–1549. doi: 10.1172/jci19906. PubMed DOI PMC

KINOUCHI K, ICHIHARA A, SANO M, SUN-WADA GH, WADA Y, KURAUCHI-MITO A, BOKUDA K, NARITA T, OSHIMA Y, SAKODA M, TAMAI Y, SATO H, FUKUDA K, ITOH H. The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes. Circ Res. 2010;107:30–34. doi: 10.1161/circresaha.110.224667. PubMed DOI

KOCKERITZ L, DOBLE B, PATEL S, WOODGETT JS. Glycogen synthase kinase-3--an overview of an over-achieving protein kinase. Curr Drug Targets. 2006;7:1377–1388. doi: 10.2174/1389450110607011377. PubMed DOI

KOUCHI M, SHIBAYAMA Y, OGAWA D, MIYAKE K, NISHIYAMA A, TAMIYA T. (Pro)renin receptor is crucial for glioma development via the Wnt/beta-catenin signaling pathway. J Neurosurg. 2017;127:819–828. doi: 10.3171/2016.9.jns16431. PubMed DOI

KROP M, LU X, DANSER AH, MEIMA ME. The (pro)renin receptor. A decade of research: what have we learned? Pflugers Arch. 2013;465:87–97. doi: 10.1007/s00424-012-1105-z. PubMed DOI PMC

LI C, SIRAGY HM. (Pro)renin receptor regulates autophagy and apoptosis in podocytes exposed to high glucose. Am J Physiol Endocrinol Metab. 2015;309:E302–E310. doi: 10.1152/ajpendo.00603.2014. PubMed DOI PMC

LI Z, ZHOU L, WANG Y, MIAO J, HONG X, HOU FF, LIU Y. (Pro)renin receptor is an amplifier of Wnt/beta-catenin signaling in kidney injury and fibrosis. J Am Soc Nephrol. 2017;28:2393–2408. doi: 10.1681/asn.2016070811. PubMed DOI PMC

LIU Y, ZHANG S, SU D, LIU J, CHENG Y, ZOU L, LI W, JIANG Y. Inhibiting (pro)renin receptor-mediated p38 MAPK signaling decreases hypoxia/reoxygenation-induced apoptosis in H9c2 cells. Mol Cell Biochem. 2015;403:267–276. doi: 10.1007/s11010-015-2356-8. PubMed DOI

MacDONALD BT, TAMAI K, HE X. Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell. 2009;17:9–26. doi: 10.1016/j.devcel.2009.06.016. PubMed DOI PMC

MAHMUD H, SILLJE HH, CANNON MV, Van GILST WH, BOER RA. Regulation of the (pro)renin-renin receptor in cardiac remodelling. J Cell Mol Med. 2012;16:722–729. doi: 10.1111/j.1582-4934.2011.01377.x. PubMed DOI PMC

MATSUI Y, TAKAGI H, QU X, ABDELLATIF M, SAKODA H, ASANO T, LEVINE B, SADOSHIMA J. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res. 2007;100:914–922. doi: 10.1161/01.res.0000261924.76669.36. PubMed DOI

NISHINO Y, WEBB IG, DAVIDSON SM, AHMED AI, CLARK JE, JACQUET S, SHAH AM, MIURA T, YELLON DM, AVKIRAN M, MARBER MS. Glycogen synthase kinase-3 inactivation is not required for ischemic preconditioning or postconditioning in the mouse. Circ Res. 2008;103:307–314. doi: 10.1161/circresaha.107.169953. PubMed DOI

NGUYEN G. Renin and prorenin receptor in hypertension: what’s new? Curr Hypertens Rep. 2011;13:79–85. doi: 10.1007/s11906-010-0172-9. PubMed DOI

NGUYEN G, DELARUE F, BURCKLE C, BOUZHIR L, GILLER T, SRAER JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest. 2002;109:1417–1427. doi: 10.1172/jci0214276. PubMed DOI PMC

PENG H, JENSEN DD, LI W, SULLIVAN MN, BULLER SA, WORKER CJ, COOPER SG, ZHENG S, EARLEY S, SIGMUND CD, FENG Y. Overexpression of the neuronal human (pro)renin receptor mediates angiotensin II-independent blood pressure regulation in the central nervous system. Am J Physiol Heart Circ Physiol. 2018;314:H580–H592. doi: 10.1152/ajpheart.00310.2017. PubMed DOI PMC

POTZ BA, SABE AA, ELMADHUN NY, CLEMENTS RT, ABID MR, SODHA NR, SELLKE FW. Calpain inhibition modulates glycogen synthase kinase 3beta pathways in ischemic myocardium: A proteomic and mechanistic analysis. J Thorac Cardiovasc Surg. 2017;153:342–357. doi: 10.1016/j.jtcvs.2016.09.087. PubMed DOI PMC

RAMKUMAR N, STUART D, ABRAHAM N, KOHAN DE. Nephron prorenin receptor deficiency alters renal medullary endothelin-1 and endothelin receptor expression. Physiol Res. 2018;67(Suppl 1):S127–S136. doi: 10.33549/physiolres.933809. PubMed DOI PMC

RIBEIRO AA, AMORIM RP, PALOMINO ZJ, De PAULA LIMA M, MORAES-SILVA IC, SOUZA LE, PESQUERO JL, IRIGOYEN MC, CASARINI DE. (Pro)renin receptor expression in myocardial infarction in transgenic mice expressing rat tonin. Int J Biol Macromol. 2018;108:817–825. doi: 10.1016/j.ijbiomac.2017.10.179. PubMed DOI

RIEDIGER F, QUACK I, QADRI F, HARTLEBEN B, PARK JK, POTTHOFF SA, SOHN D, SIHN G, ROUSSELLE A, FOKUHL V, MASCHKE U, PURFURST B, SCHNEIDER W, RUMP LC, LUFT FC, DECHEND R, BADER M, HUBER TB, NGUYEN G, MULLER DN. Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol. 2011;22:2193–2202. doi: 10.1681/asn.2011020200. PubMed DOI PMC

ROMERO M, SABATE-PEREZ A, FRANCIS VA, CASTRILLON-RODRIGUEZ I, DIAZ-RAMOS A, SANCHEZ-FEUTRIE M, DURAN X, PALACIN M, MORENO-NAVARRETE JM, GUSTAFSON B, HAMMARSTEDT A, FERNANDEZ-REAL JM, VENDRELL J, SMITH U, ZORZANO A. TP53INP2 regulates adiposity by activating beta-catenin through autophagy-dependent sequestration of GSK3beta. Nat Cell Biol. 2018;20:443–454. doi: 10.1038/s41556-018-0072-9. PubMed DOI

SHIBAYAMA Y, FUJIMORI T, NGUYEN G, HIROSE T, TOTSUNE K, ICHIHARA A, KITADA K, NAKANO D, KOBORI H, KOHNO M, MASAKI T, SUZUKI Y, YACHIDA S, NISHIYAMA A. (Pro)renin receptor is crucial for Wnt/beta-catenin-dependent genesis of pancreatic ductal adenocarcinoma. Sci Rep. 2015;5:8854. doi: 10.1038/srep08854. PubMed DOI PMC

SINGH KK, YANAGAWA B, QUAN A, WANG R, GARG A, KHAN R, PAN Y, WHEATCROFT MD, LOVREN F, TEOH H, VERMA S. Autophagy gene fingerprint in human ischemia and reperfusion. J Thorac Cardiovasc Surg. 2014;147:1065–1072.e1. doi: 10.1016/j.jtcvs.2013.04.042. PubMed DOI

THIRUNAVUKKARASU SELVARAJU V, TAPIAS L, SANCHEZ JA, PALESTY JA, MAULIK N. Protective effects of Phyllanthus emblica against myocardial ischemia-reperfusion injury: the role of PI3-kinase/glycogen synthase kinase 3beta/beta-catenin pathway. J Physiol Biochem. 2015;71:623–633. doi: 10.1007/s13105-015-0426-8. PubMed DOI

YAHIRO E, IDEISHI M, WANG LX, URATA H, KUMAGAI K, ARAKAWA K, SAKU K. Reperfusion-induced arrhythmias are suppressed by inhibition of the angiotensin II type 1 receptor. Cardiology. 2003;99:61–67. doi: 10.1159/000069722. PubMed DOI

YELLON DM, HAUSENLOY DJ. Myocardial reperfusion injury. N Engl J Med. 2007;357:1121–1135. doi: 10.1056/nejmra071667. PubMed DOI

ZHOU A, CARRELL RW, MURPHY MP, WEI Z, YAN Y, STANLEY PL, STEIN PE, BROUGHTON PIPKIN F, READ RJ. A redox switch in angiotensinogen modulates angiotensin release. Nature. 2010;468:108–111. doi: 10.1038/nature09505. PubMed DOI PMC

ZHOU H, ZHANG Y, HU S, SHI C, ZHU P, MA Q, JIN Q, CAO F, TIAN F, CHEN Y. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTP-mitophagy axis. J Pineal Res. 2017;63 doi: 10.1111/jpi.12413. PubMed DOI PMC

ZHU B, SUN Y, SIEVERS RE, BROWNE AE, PULUKURTHY S, SUDHIR K, LEE RJ, CHOU TM, CHATTERJEE K, PARMLEY WW. Comparative effects of pretreatment with captopril and losartan on cardiovascular protection in a rat model of ischemia-reperfusion. J Am Coll Cardiol. 2000;35:787–795. doi: 10.1016/s0735-1097(99)00592-6. PubMed DOI

miR-431-5p regulates apoptosis of cardiomyocytes after acute myocardial infarction via targeting selenoprotein T