Skip to main content

Advertisement

SpringerLink
Log in

Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Despite improved treatment options myocardial infarction (MI) is still a leading cause of mortality and morbidity worldwide. Remote ischemic preconditioning (RIPC) is a mechanistic process that reduces myocardial infarction size and protects against ischemia reperfusion (I/R) injury. The zinc finger transcription factor early growth response-1 (Egr-1) is integral to the biological response to I/R, as its upregulation mediates the increased expression of inflammatory and prothrombotic processes. We aimed to determine the association and/or role of Egr-1 expression with the molecular mechanisms controlling the cardioprotective effects of RIPC. This study used H9C2 cells in vitro and a rat model of cardiac ischemia reperfusion (I/R) injury. We silenced Egr-1 with DNAzyme (ED5) in vitro and in vivo, before three cycles of RIPC consisting of alternating 5 min hypoxia and normoxia in cells or hind-limb ligation and release in the rat, followed by hypoxic challenge in vitro and I/R injury in vivo. Post-procedure, ED5 administration led to a significant increase in infarct size compared to controls (65.90 ± 2.38% vs. 41.00 ± 2.83%, p < 0.0001) following administration prior to RIPC in vivo, concurrent with decreased plasma IL-6 levels (118.30 ± 4.30 pg/ml vs. 130.50 ± 1.29 pg/ml, p < 0.05), downregulation of the cardioprotective JAK–STAT pathway, and elevated myocardial endothelial dysfunction. In vitro, ED5 administration abrogated IL-6 mRNA expression in H9C2 cells subjected to RIPC (0.95 ± 0.20 vs. 6.08 ± 1.40-fold relative to the control group, p < 0.05), resulting in increase in apoptosis (4.76 ± 0.70% vs. 2.23 ± 0.34%, p < 0.05) and loss of mitochondrial membrane potential (0.57 ± 0.11% vs. 1.0 ± 0.14%-fold relative to control, p < 0.05) in recipient cells receiving preconditioned media from the DNAzyme treated donor cells. This study suggests that Egr-1 functions as a master regulator of remote preconditioning inducing a protective effect against myocardial I/R injury through IL-6-dependent JAK–STAT signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Abas L, Bogoyevitch MA, Guppy M (2000) Mitochondrial ATP production is necessary for activation of the extracellular-signal-regulated kinases during ischaemia/reperfusion in rat myocyte-derived H9c2 cells. Biochem J 349:119–126. https://doi.org/10.1042/0264-6021:3490119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Abu-Amara M, Yang SY, Quaglia A, Rowley P, Tapuria N, Seifalian AM, Fuller BJ, Davidson BR (2011) Effect of remote ischemic preconditioning on liver ischemia/reperfusion injury using a new mouse model. Liver Transpl 17:70–82. https://doi.org/10.1002/lt.22204

    Article  PubMed  Google Scholar 

  3. Aebert H, Cornelius T, Ehr T, Holmer SR, Birnbaum DE, Riegger GA, Schunkert H (1997) Expression of immediate early genes after cardioplegic arrest and reperfusion. Ann Thorac Surg 63:1669–1675

    Article  CAS  Google Scholar 

  4. Ahmed RM, el Mohamed HA, Ashraf M, Maithili S, Nabil F, Rami R, Mohamed TI (2013) Effect of remote ischemic preconditioning on serum troponin T level following elective percutaneous coronary intervention. Catheter Cardiovasc Interv 82:E647–E653. https://doi.org/10.1002/ccd.24825

    Article  PubMed  Google Scholar 

  5. Ali ZA, Callaghan CJ, Lim E, Ali AA, Nouraei SA, Akthar AM, Boyle JR, Varty K, Kharbanda RK, Dutka DP, Gaunt ME (2007) Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial. Circulation 116:I98–I105. https://doi.org/10.1161/circulationaha.106.679167

    Article  PubMed  Google Scholar 

  6. Beauchamp P, Richard V, Tamion F, Lallemand F, Lebreton JP, Vaudry H, Daveau M, Thuillez C (1999) Protective effects of preconditioning in cultured rat endothelial cells: effects on neutrophil adhesion and expression of ICAM-1 after anoxia and reoxygenation. Circulation 100:541–546. https://doi.org/10.1161/01.cir.100.5.541

    Article  CAS  PubMed  Google Scholar 

  7. Bhindi R, Fahmy RG, Lowe HC, Chesterman CN, Dass CR, Cairns MJ, Saravolac EG, Sun LQ, Khachigian LM (2007) Brothers in arms: DNA enzymes, short interfering RNA, and the emerging wave of small-molecule nucleic acid-based gene-silencing strategies. Am J Pathol 171:1079–1088. https://doi.org/10.2353/ajpath.2007.070120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Bhindi R, Fahmy RG, McMahon AC, Khachigian LM, Lowe HC (2012) Intracoronary delivery of DNAzymes targeting human EGR-1 reduces infarct size following myocardial ischaemia reperfusion. J Pathol 227:157–164. https://doi.org/10.1002/path.2991

    Article  CAS  PubMed  Google Scholar 

  9. Bhindi R, Khachigian LM, Lowe HC (2006) DNAzymes targeting the transcription factor Egr-1 reduce myocardial infarct size following ischemia-reperfusion in rats. J Thromb Haemost 4:1479–1483. https://doi.org/10.1111/j.1538-7836.2006.02022.x

    Article  CAS  PubMed  Google Scholar 

  10. Billah M, Ridiandries A, Allahwala U, Mudaliar H, Dona A, Hunyor S, Khachigian LM, Bhindi R (2019) Circulating mediators of remote ischemic preconditioning: search for the missing link between non-lethal ischemia and cardioprotection. Oncotarget 10:216–244. https://doi.org/10.18632/oncotarget.26537

    Article  PubMed  PubMed Central  Google Scholar 

  11. Bonavita F, Stefanelli C, Giordano E, Columbaro M, Facchini A, Bonafe F, Caldarera CM, Guarnieri C (2003) H9c2 cardiac myoblasts undergo apoptosis in a model of ischemia consisting of serum deprivation and hypoxia: inhibition by PMA. FEBS Lett 536:85–91. https://doi.org/10.1016/s0014-5793(03)00029-2

    Article  CAS  PubMed  Google Scholar 

  12. Bonventre JV, Sukhatme VP, Bamberger M, Ouellette AJ, Brown D (1991) Localization of the protein product of the immediate early growth response gene, Egr-1, in the kidney after ischemia and reperfusion. Cell Regul 2:251–260. https://doi.org/10.1091/mbc.2.3.251

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Botker HE, Hausenloy D, Andreadou I, Antonucci S, Boengler K, Davidson SM, Deshwal S, Devaux Y, Di Lisa F, Di Sante M, Efentakis P, Femmino S, Garcia-Dorado D, Giricz Z, Ibanez B, Iliodromitis E, Kaludercic N, Kleinbongard P, Neuhauser M, Ovize M, Pagliaro P, Rahbek-Schmidt M, Ruiz-Meana M, Schluter KD, Schulz R, Skyschally A, Wilder C, Yellon DM, Ferdinandy P, Heusch G (2018) Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection. Basic Res Cardiol 113:39. https://doi.org/10.1007/s00395-018-0696-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Botker HE, Kharbanda R, Schmidt MR, Bottcher M, Kaltoft AK, Terkelsen CJ, Munk K, Andersen NH, Hansen TM, Trautner S, Lassen JF, Christiansen EH, Krusell LR, Kristensen SD, Thuesen L, Nielsen SS, Rehling M, Sorensen HT, Redington AN, Nielsen TT (2010) Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: a randomised trial. Lancet 375:727–734. https://doi.org/10.1016/S0140-6736(09)62001-8

    Article  PubMed  Google Scholar 

  15. Brand T, Sharma HS, Fleischmann KE, Duncker DJ, McFalls EO, Verdouw PD, Schaper W (1992) Proto-oncogene expression in porcine myocardium subjected to ischemia and reperfusion. Circ Res 71:1351–1360

    Article  CAS  Google Scholar 

  16. Breivik L, Helgeland E, Aarnes EK, Mrdalj J, Jonassen AK (2011) Remote postconditioning by humoral factors in effluent from ischemic preconditioned rat hearts is mediated via PI3K/Akt-dependent cell-survival signaling at reperfusion. Basic Res Cardiol 106:135–145. https://doi.org/10.1007/s00395-010-0133-0

    Article  CAS  PubMed  Google Scholar 

  17. Cairns MJ, Hopkins TM, Witherington C, Wang L, Sun LQ (1999) Target site selection for an RNA-cleaving catalytic DNA. Nat Biotechnol 17:480–486. https://doi.org/10.1038/8658

    Article  CAS  PubMed  Google Scholar 

  18. Chen Y, Lui VC, Rooijen NV, Tam PK (2004) Depletion of intestinal resident macrophages prevents ischaemia reperfusion injury in gut. Gut 53:1772–1780. https://doi.org/10.1136/gut.2003.034868

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Cheung MM, Kharbanda RK, Konstantinov IE, Shimizu M, Frndova H, Li J, Holtby HM, Cox PN, Smallhorn JF, Van Arsdell GS, Redington AN (2006) Randomized controlled trial of the effects of remote ischemic preconditioning on children undergoing cardiac surgery: first clinical application in humans. J Am Coll Cardiol 47:2277–2282. https://doi.org/10.1016/j.jacc.2006.01.066

    Article  PubMed  Google Scholar 

  20. Chouchani ET, Methner C, Nadtochiy SM, Logan A, Pell VR, Ding S, James AM, Cocheme HM, Reinhold J, Lilley KS, Partridge L, Fearnley IM, Robinson AJ, Hartley RC, Smith RA, Krieg T, Brookes PS, Murphy MP (2013) Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I. Nat Med 19:753–759. https://doi.org/10.1038/nm.3212

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cocheme HM, Logan A, Prime TA, Abakumova I, Quin C, McQuaker SJ, Patel JV, Fearnley IM, James AM, Porteous CM, Smith RA, Hartley RC, Partridge L, Murphy MP (2012) Using the mitochondria-targeted ratiometric mass spectrometry probe MitoB to measure H2O2 in living Drosophila. Nat Protoc 7:946–958. https://doi.org/10.1038/nprot.2012.035

    Article  CAS  PubMed  Google Scholar 

  22. Crompton M (1999) The mitochondrial permeability transition pore and its role in cell death. Biochem J 341(Pt 2):233–249

    Article  CAS  PubMed Central  Google Scholar 

  23. Dass CR, Saravolac EG, Li Y, Sun LQ (2002) Cellular uptake, distribution, and stability of 10-23 deoxyribozymes. Antisense Nucleic Acid Drug Dev 12:289–299. https://doi.org/10.1089/108729002761381276

    Article  CAS  PubMed  Google Scholar 

  24. Davidovich P, Kearney CJ, Martin SJ (2014) Inflammatory outcomes of apoptosis, necrosis and necroptosis. Biol Chem 395:1163–1171. https://doi.org/10.1515/hsz-2014-0164

    Article  CAS  PubMed  Google Scholar 

  25. Davidson SM, Arjun S, Basalay MV, Bell RM, Bromage DI, Botker HE, Carr RD, Cunningham J, Ghosh AK, Heusch G, Ibanez B, Kleinbongard P, Lecour S, Maddock H, Ovize M, Walker M, Wiart M, Yellon DM (2018) The 10th Biennial Hatter Cardiovascular Institute workshop: cellular protection-evaluating new directions in the setting of myocardial infarction, ischaemic stroke, and cardio-oncology. Basic Res Cardiol 113:43. https://doi.org/10.1007/s00395-018-0704-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Dawn B, Xuan Y, Rezazadeh A, Stein A, Hunt G, Wu W, Tan W, Bolli R (2004) IL-6 plays an obligatory role in late preconditioning via JAK-STAT signaling and upregulation of iNOS and COX-2. Cardiovasc Res 64:61–71. https://doi.org/10.1016/j.cardiores.2004.05.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Dickson EW, Blehar DJ, Carraway RE, Heard SO, Steinberg G, Przyklenk K (2001) Naloxone blocks transferred preconditioning in isolated rabbit hearts. J Mol Cell Cardiol 33:1751–1756. https://doi.org/10.1006/jmcc.2001.1436

    Article  CAS  PubMed  Google Scholar 

  28. Dickson EW, Porcaro WA, Fenton RA, Heard SO, Reindhardt CP, Renzi FP, Przyklenk K (2000) “Preconditioning at a distance” in the isolated rabbit heart. Acad Emerg Med 7:311–317

    Article  CAS  Google Scholar 

  29. Dickson EW, Reinhardt CP, Renzi FP, Becker RC, Porcaro WA, Heard SO (1999) Ischemic preconditioning may be transferable via whole blood transfusion: preliminary evidence. J Thromb Thrombolysis 8:123–129

    Article  CAS  Google Scholar 

  30. Ferdinandy P, Hausenloy DJ, Heusch G, Baxter GF, Schulz R (2014) Interaction of risk factors, comorbidities, and comedications with ischemia/reperfusion injury and cardioprotection by preconditioning, postconditioning, and remote conditioning. Pharmacol Rev 66:1142–1174. https://doi.org/10.1124/pr.113.008300

    Article  CAS  PubMed  Google Scholar 

  31. Gashler A, Sukhatme VP (1995) Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Mol Biol Transl Sci 50:191–224

    CAS  Google Scholar 

  32. Gaspar A, Lourenco AP, Pereira MA, Azevedo P, Roncon-Albuquerque R Jr, Marques J, Leite-Moreira AF (2018) Randomized controlled trial of remote ischaemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty (RIC-STEMI). Basic Res Cardiol 113:14. https://doi.org/10.1007/s00395-018-0672-3

    Article  PubMed  Google Scholar 

  33. Gedik N, Kottenberg E, Thielmann M, Frey UH, Jakob H, Peters J, Heusch G, Kleinbongard P (2017) Potential humoral mediators of remote ischemic preconditioning in patients undergoing surgical coronary revascularization. Sci Rep 7:12660. https://doi.org/10.1038/s41598-017-12833-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Gedik N, Thielmann M, Kottenberg E, Peters J, Jakob H, Heusch G, Kleinbongard P (2014) No evidence for activated autophagy in left ventricular myocardium at early reperfusion with protection by remote ischemic preconditioning in patients undergoing coronary artery bypass grafting. PLoS One 9:e96567. https://doi.org/10.1371/journal.pone.0096567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gent S, Skyschally A, Kleinbongard P, Heusch G (2017) lschemic preconditioning in pigs: a causal role for signal transducer and activator of transcription 3. Am J Physiol Heart Circ Physiol 312:H478–H484. https://doi.org/10.1152/ajpheart.00749.2016

    Article  PubMed  Google Scholar 

  36. Goldman A, Harper S, Speicher DW (2016) Detection of proteins on blot membranes. Curr Protoc Protein Sci 86:10. https://doi.org/10.1002/cpps.15

    Article  PubMed  PubMed Central  Google Scholar 

  37. Gottlieb RA (2011) Cell death pathways in acute ischemia/reperfusion injury. J Cardiovasc Pharmacol Ther 16:233–238. https://doi.org/10.1177/1074248411409581

    Article  CAS  PubMed  Google Scholar 

  38. Guimaraes Filho MA, Cortez E, Garcia-Souza EP, Soares Vde M, Moura AS, Carvalho L, Maya MC, Pitombo MB (2015) Effect of remote ischemic preconditioning in the expression of IL-6 and IL-10 in a rat model of liver ischemia-reperfusion injury. Acta Cirurgica Brasileira 30:452–460. https://doi.org/10.1590/S0102-865020150070000002

    Article  PubMed  Google Scholar 

  39. Hausenloy DJ, Kharbanda RK, Moller UK, Ramlall M, Aaroe J, Butler R, Bulluck H, Clayton T, Dana A, Dodd M, Engstrom T, Evans R, Lassen JF, Christensen EF, Garcia-Ruiz JM, Gorog DA, Hjort J, Houghton RF, Ibanez B, Knight R, Lippert FK, Lonborg JT, Maeng M, Milasinovic D, More R, Nicholas JM, Jensen LO, Perkins A, Radovanovic N, Rakhit RD, Ravkilde J, Ryding AD, Schmidt MR, Riddervold IS, Sorensen HT, Stankovic G, Varma M, Webb I, Terkelsen CJ, Greenwood JP, Yellon DM, Botker HE, Investigators C-E-P (2019) Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet 394:1415–1424. https://doi.org/10.1016/S0140-6736(19)32039-2

    Article  PubMed  PubMed Central  Google Scholar 

  40. Hausenloy DJ, Mwamure PK, Venugopal V, Harris J, Barnard M, Grundy E, Ashley E, Vichare S, Di Salvo C, Kolvekar S, Hayward M, Keogh B, MacAllister RJ, Yellon DM (2007) Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: a randomised controlled trial. Lancet 370:575–579. https://doi.org/10.1016/S0140-6736(07)61296-3

    Article  PubMed  Google Scholar 

  41. Heusch G (2018) 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol 113:15. https://doi.org/10.1007/s00395-018-0673-2

    Article  PubMed  Google Scholar 

  42. Heusch G (2016) The coronary circulation as a target of cardioprotection. Circ Res 118:1643–1658. https://doi.org/10.1161/CIRCRESAHA.116.308640

    Article  CAS  PubMed  Google Scholar 

  43. Heusch G (2019) Coronary microvascular obstruction: the new frontier in cardioprotection. Basic Res Cardiol 114:45. https://doi.org/10.1007/s00395-019-0756-8

    Article  CAS  PubMed  Google Scholar 

  44. Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. https://doi.org/10.1161/CIRCRESAHA.116.305348

    Article  CAS  PubMed  Google Scholar 

  45. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195. https://doi.org/10.1016/j.jacc.2014.10.031

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Heusch G, Kleinbongard P, Skyschally A, Levkau B, Schulz R, Erbel R (2012) The coronary circulation in cardioprotection: more than just one confounder. Cardiovasc Res 94:237–245. https://doi.org/10.1093/cvr/cvr271

    Article  CAS  PubMed  Google Scholar 

  47. Heusch G, Musiolik J, Gedik N, Skyschally A (2011) Mitochondrial STAT3 activation and cardioprotection by ischemic postconditioning in pigs with regional myocardial ischemia/reperfusion. Circ Res 109:1302–1308. https://doi.org/10.1161/CIRCRESAHA.111.255604

    Article  CAS  PubMed  Google Scholar 

  48. Heusch G, Musiolik J, Kottenberg E, Peters J, Jakob H, Thielmann M (2012) STAT5 activation and cardioprotection by remote ischemic preconditioning in humans: short communication. Circ Res 110:111–115. https://doi.org/10.1161/CIRCRESAHA.111.259556

    Article  CAS  PubMed  Google Scholar 

  49. Heusch G, Rassaf T (2016) Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res 119:676–695. https://doi.org/10.1161/CIRCRESAHA.116.308736

    Article  CAS  PubMed  Google Scholar 

  50. Hoole SP, Heck PM, Sharples L, Khan SN, Duehmke R, Densem CG, Clarke SC, Shapiro LM, Schofield PM, O’Sullivan M, Dutka DP (2009) Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study: a prospective, randomized control trial. Circulation 119:820–827. https://doi.org/10.1161/CIRCULATIONAHA.108.809723

    Article  PubMed  Google Scholar 

  51. Hu Z, Hu S, Yang S, Chen M, Zhang P, Liu J, Abbott GW (2016) Remote liver ischemic preconditioning protects against sudden cardiac death via an ERK/GSK-3beta-dependent mechanism. PLoS ONE 11:e0165123. https://doi.org/10.1371/journal.pone.0165123

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ikeda U, Ohkawa F, Seino Y, Yamamoto K, Hidaka Y, Kasahara T, Kawai T, Shimada K (1992) Serum interleukin 6 levels become elevated in acute myocardial infarction. J Mol Cell Cardiol 24:579–584

    Article  CAS  Google Scholar 

  53. Jonchere B, Belanger A, Guette C, Barre B, Coqueret O (2013) STAT3 as a new autophagy regulator. JAKSTAT 2:e24353. https://doi.org/10.4161/jkst.24353

    Article  PubMed  PubMed Central  Google Scholar 

  54. Khachigian LM (2006) Early growth response-1 in cardiovascular pathobiology. Circ Res 98:186–191. https://doi.org/10.1161/01.RES.0000200177.53882.c3

    Article  CAS  PubMed  Google Scholar 

  55. Kimes BW, Brandt BL (1976) Properties of a clonal muscle cell line from rat heart. Exp Cell Res 98:367–381

    Article  CAS  Google Scholar 

  56. Kleinbongard P, Amanakis G, Skyschally A, Heusch G (2018) Reflection of cardioprotection by remote ischemic perconditioning in attenuated ST-segment elevation during ongoing coronary occlusion in pigs: evidence for cardioprotection from ischemic injury. Circ Res 122:1102–1108. https://doi.org/10.1161/CIRCRESAHA.118.312784

    Article  CAS  PubMed  Google Scholar 

  57. Kleinbongard P, Botker HE, Ovize M, Hausenloy DJ, Heusch G (2019) Co-morbidities and co-medications as confounders of cardioprotection—does it matter in the clinical setting? Br J Pharmacol. https://doi.org/10.1111/bph.14839

    Article  PubMed  Google Scholar 

  58. Kleinbongard P, Skyschally A, Gent S, Pesch M, Heusch G (2018) STAT3 as a common signal of ischemic conditioning: a lesson on “rigor and reproducibility” in preclinical studies on cardioprotection. Basic Res Cardiol 113:3. https://doi.org/10.1007/s00395-017-0660-z

    Article  CAS  PubMed  Google Scholar 

  59. Kleinbongard P, Skyschally A, Heusch G (2017) Cardioprotection by remote ischemic conditioning and its signal transduction. Pflugers Arch 469:159–181. https://doi.org/10.1007/s00424-016-1922-6

    Article  CAS  PubMed  Google Scholar 

  60. Konstantinov IE, Arab S, Li J, Coles JG, Boscarino C, Mori A, Cukerman E, Dawood F, Cheung MM, Shimizu M, Liu PP, Redington AN (2005) The remote ischemic preconditioning stimulus modifies gene expression in mouse myocardium. J Thorac Cardiovasc Surg 130:1326–1332. https://doi.org/10.1016/j.jtcvs.2005.03.050

    Article  CAS  PubMed  Google Scholar 

  61. Kopantzev Y, Heller M, Swaminathan N, Rudikoff S (2002) IL-6 mediated activation of STAT3 bypasses Janus kinases in terminally differentiated B lineage cells. Oncogene 21:6791–6800. https://doi.org/10.1038/sj.onc.1205815

    Article  CAS  PubMed  Google Scholar 

  62. Koshinuma S, Miyamae M, Kaneda K, Kotani J, Figueredo VM (2014) Combination of necroptosis and apoptosis inhibition enhances cardioprotection against myocardial ischemia-reperfusion injury. J Anesth 28:235–241. https://doi.org/10.1007/s00540-013-1716-3

    Article  PubMed  Google Scholar 

  63. Kroemer G, Dallaporta B, Resche-Rigon M (1998) The mitochondrial death/life regulator in apoptosis and necrosis. Annu Rev Physiol 60:619–642. https://doi.org/10.1146/annurev.physiol.60.1.619

    Article  CAS  PubMed  Google Scholar 

  64. Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6:513–519. https://doi.org/10.1038/74994

    Article  CAS  PubMed  Google Scholar 

  65. Kuznetsov AV, Javadov S, Sickinger S, Frotschnig S, Grimm M (2015) H9c2 and HL-1 cells demonstrate distinct features of energy metabolism, mitochondrial function and sensitivity to hypoxia-reoxygenation. Biochim Biophys Acta 1853:276–284. https://doi.org/10.1016/j.bbamcr.2014.11.015

    Article  CAS  PubMed  Google Scholar 

  66. Lanza IR, Nair KS (2010) Mitochondrial metabolic function assessed in vivo and in vitro. Curr Opin Clin Nutr Metab Care 13:511–517. https://doi.org/10.1097/MCO.0b013e32833cc93d

    Article  PubMed  PubMed Central  Google Scholar 

  67. Lawson C, Wolf S (2009) ICAM-1 signaling in endothelial cells. Pharmacol Rep 61:22–32. https://doi.org/10.1016/s1734-1140(09)70004-0

    Article  CAS  PubMed  Google Scholar 

  68. Liang Y, Li YP, He F, Liu XQ, Zhang JY (2015) Long-term, regular remote ischemic preconditioning improves endothelial function in patients with coronary heart disease. Braz J Med Biol Res 48:568–576. https://doi.org/10.1590/1414-431X20144452

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Liauw SK, Rubin BB, Lindsay TF, Romaschin AD, Walker PM (1996) Sequential ischemia/reperfusion results in contralateral skeletal muscle salvage. Am J Physiol 270:H1407–H1413

    CAS  PubMed  Google Scholar 

  70. Lindsey ML, Bolli R, Canty JM Jr, Du XJ, Frangogiannis NG, Frantz S, Gourdie RG, Holmes JW, Jones SP, Kloner RA, Lefer DJ, Liao R, Murphy E, Ping P, Przyklenk K, Recchia FA, Schwartz Longacre L, Ripplinger CM, Van Eyk JE, Heusch G (2018) Guidelines for experimental models of myocardial ischemia and infarction. Am J Physiol Heart Circ Physiol 314:H812–H838. https://doi.org/10.1152/ajpheart.00335.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Loukogeorgakis SP, Panagiotidou AT, Broadhead MW, Donald A, Deanfield JE, MacAllister RJ (2005) Remote ischemic preconditioning provides early and late protection against endothelial ischemia-reperfusion injury in humans: role of the autonomic nervous system. J Am Coll Cardiol 46:450–456. https://doi.org/10.1016/j.jacc.2005.04.044

    Article  CAS  PubMed  Google Scholar 

  72. Lowe HC, Fahmy RG, Kavurma MM, Baker A, Chesterman CN, Khachigian LM (2001) Catalytic oligodeoxynucleotides define a key regulatory role for early growth response factor-1 in the porcine model of coronary in-stent restenosis. Circ Res 89:670–677. https://doi.org/10.1161/hh2001.097867

    Article  CAS  PubMed  Google Scholar 

  73. Luig M, Kluger MA, Goerke B, Meyer M, Nosko A, Yan I, Scheller J, Mittrucker HW, Rose-John S, Stahl RA, Panzer U, Steinmetz OM (2015) Inflammation-induced IL-6 functions as a natural brake on macrophages and limits GN. J Am Soc Nephrol 26:1597–1607. https://doi.org/10.1681/ASN.2014060620

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Manchurov V, Ryazankina N, Khmara T, Skrypnik D, Reztsov R, Vasilieva E, Shpektor A (2014) Remote ischemic preconditioning and endothelial function in patients with acute myocardial infarction and primary PCI. Am J Med 127:670–673. https://doi.org/10.1016/j.amjmed.2014.02.012

    Article  PubMed  Google Scholar 

  75. Marubayashi S, Oshiro Y, Maeda T, Fukuma K, Okada K, Hinoi T, Ikeda M, Yamada K, Itoh H, Dohi K (1997) Protective effect of monoclonal antibodies to adhesion molecules on rat liver ischemia-reperfusion injury. Surgery 122:45–52

    Article  CAS  Google Scholar 

  76. Matsushita K, Iwanaga S, Oda T, Kimura K, Shimada M, Sano M, Umezawa A, Hata J, Ogawa S (2005) Interleukin-6/soluble interleukin-6 receptor complex reduces infarct size via inhibiting myocardial apoptosis. Lab Invest 85:1210–1223. https://doi.org/10.1038/labinvest.3700322

    Article  CAS  PubMed  Google Scholar 

  77. McGinnis GR, Ballmann C, Peters B, Nanayakkara G, Roberts M, Amin R, Quindry JC (2015) Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury. Am J Physiol Heart Circ Physiol 308:H1423–H1433. https://doi.org/10.1152/ajpheart.00850.2014

    Article  CAS  PubMed  Google Scholar 

  78. Mejia-Alvarez R, Tomaselli GF, Marban E (1994) Simultaneous expression of cardiac and skeletal muscle isoforms of the L-type Ca2 + channel in a rat heart muscle cell line. J Physiol 478(Pt 2):315–329. https://doi.org/10.1113/jphysiol.1994.sp020252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Miyao Y, Yasue H, Ogawa H, Misumi I, Masuda T, Sakamoto T, Morita E (1993) Elevated plasma interleukin-6 levels in patients with acute myocardial infarction. Am Heart J 126:1299–1304

    Article  CAS  Google Scholar 

  80. Mocanu MM, Baxter GF, Yue Y, Critz SD, Yellon DM (2000) The p38 MAPK inhibitor, SB203580, abrogates ischaemic preconditioning in rat heart but timing of administration is critical. Basic Res Cardiol 95:472–478. https://doi.org/10.1007/s003950070023

    Article  CAS  PubMed  Google Scholar 

  81. Mudaliar H, Rayner B, Billah M, Kapoor N, Lay W, Dona A, Bhindi R (2017) Remote ischemic preconditioning attenuates EGR-1 expression following myocardial ischemia reperfusion injury through activation of the JAK-STAT pathway. Int J Cardiol 228:729–741. https://doi.org/10.1016/j.ijcard.2016.11.198

    Article  CAS  PubMed  Google Scholar 

  82. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136. https://doi.org/10.1161/01.cir.74.5.1124

    Article  CAS  PubMed  Google Scholar 

  83. Nakano H, Kuzume M, Namatame K, Yamaguchi M, Kumada K (1995) Efficacy of intraportal injection of anti-ICAM-1 monoclonal antibody against liver cell injury following warm ischemia in the rat. Am J Surg 170:64–66

    Article  CAS  Google Scholar 

  84. Nguyen HQ, Hoffman-Liebermann B, Liebermann DA (1993) The zinc finger transcription factor Egr-1 is essential for and restricts differentiation along the macrophage lineage. Cell 72:197–209

    Article  CAS  Google Scholar 

  85. Niccoli G, Montone RA, Ibanez B, Thiele H, Crea F, Heusch G, Bulluck H, Hausenloy DJ, Berry C, Stiermaier T, Camici PG, Eitel I (2019) Optimized treatment of ST-elevation myocardial infarction. Circ Res 125:245–258. https://doi.org/10.1161/CIRCRESAHA.119.315344

    Article  CAS  PubMed  Google Scholar 

  86. Ouellette AJ, Malt RA, Sukhatme VP, Bonventre JV (1990) Expression of two “immediate early” genes, Egr-1 and c-fos, in response to renal ischemia and during compensatory renal hypertrophy in mice. J Clin Invest 85:766–771. https://doi.org/10.1172/JCI114502

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Pavon N, Martinez-Abundis E, Hernandez L, Gallardo-Perez JC, Alvarez-Delgado C, Cerbon M, Perez-Torres I, Aranda A, Chavez E (2012) Sexual hormones: effects on cardiac and mitochondrial activity after ischemia-reperfusion in adult rats. Gender difference. J Steroid Biochem Mol Biol 132:135–146. https://doi.org/10.1016/j.jsbmb.2012.05.003

    Article  CAS  PubMed  Google Scholar 

  88. Pepe S, Liaw NY, Hepponstall M, Sheeran FL, Yong MS, d’Udekem Y, Cheung MM, Konstantinov IE (2013) Effect of remote ischemic preconditioning on phosphorylated protein signaling in children undergoing tetralogy of Fallot repair: a randomized controlled trial. J Am Heart Assoc 2:e000095. https://doi.org/10.1161/JAHA.113.000095

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Peters M, Jacobs S, Ehlers M, Vollmer P, Mullberg J, Wolf E, Brem G, Meyer zum Buschenfelde KH, Rose-John S (1996) The function of the soluble interleukin 6 (IL-6) receptor in vivo: sensitization of human soluble IL-6 receptor transgenic mice towards IL-6 and prolongation of the plasma half-life of IL-6. J Exp Med 183:1399–1406

    Article  CAS  Google Scholar 

  90. Przyklenk K, Dong Y, Undyala VV, Whittaker P (2012) Autophagy as a therapeutic target for ischaemia/reperfusion injury? Concepts, controversies, and challenges. Cardiovasc Res 94:197–205. https://doi.org/10.1093/cvr/cvr358

    Article  CAS  PubMed  Google Scholar 

  91. Przyklenk K, Whittaker P (2011) Remote ischemic preconditioning: current knowledge, unresolved questions, and future priorities. J Cardiovasc Pharmacol Ther 16:255–259. https://doi.org/10.1177/1074248411409040

    Article  PubMed  Google Scholar 

  92. Ratcliffe PJ (2007) HIF-1 and HIF-2: working alone or together in hypoxia? J Clin Invest 117:862–865. https://doi.org/10.1172/JCI31750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Rayner BS, Figtree GA, Sabaretnam T, Shang P, Mazhar J, Weaver JC, Lay WN, Witting PK, Hunyor SN, Grieve SM, Khachigian LM, Bhindi R (2013) Selective inhibition of the master regulator transcription factor Egr-1 with catalytic oligonucleotides reduces myocardial injury and improves left ventricular systolic function in a preclinical model of myocardial infarction. J Am Heart Assoc 2:e000023. https://doi.org/10.1161/JAHA.113.000023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Rochitte CE, Lima JA, Bluemke DA, Reeder SB, McVeigh ER, Furuta T, Becker LC, Melin JA (1998) Magnitude and time course of microvascular obstruction and tissue injury after acute myocardial infarction. Circulation 98:1006–1014. https://doi.org/10.1161/01.cir.98.10.1006

    Article  CAS  PubMed  Google Scholar 

  95. Rohailla S, Clarizia N, Sourour M, Sourour W, Gelber N, Wei C, Li J, Redington AN (2014) Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling. PLoS One 9:e111291. https://doi.org/10.1371/journal.pone.0111291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Romano M, Sironi M, Toniatti C, Polentarutti N, Fruscella P, Ghezzi P, Faggioni R, Luini W, van Hinsbergh V, Sozzani S, Bussolino F, Poli V, Ciliberto G, Mantovani A (1997) Role of IL-6 and its soluble receptor in induction of chemokines and leukocyte recruitment. Immunity 6:315–325

    Article  CAS  Google Scholar 

  97. Saeed WK, Jun DW, Jang K, Chae YJ, Lee JS, Kang HT (2017) Does necroptosis have a crucial role in hepatic ischemia-reperfusion injury? PLoS One 12:e0184752. https://doi.org/10.1371/journal.pone.0184752

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Saini HK, Xu YJ, Zhang M, Liu PP, Kirshenbaum LA, Dhalla NS (2005) Role of tumour necrosis factor-alpha and other cytokines in ischemia-reperfusion-induced injury in the heart. Exp Clin Cardiol 10:213–222

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Scheller J, Rose-John S (2006) Interleukin-6 and its receptor: from bench to bedside. Med Microbiol Immunol 195:173–183. https://doi.org/10.1007/s00430-006-0019-9

    Article  CAS  PubMed  Google Scholar 

  100. Schulz R, Belosjorow S, Gres P, Jansen J, Michel MC, Heusch G (2002) p38 MAP kinase is a mediator of ischemic preconditioning in pigs. Cardiovasc Res 55:690–700. https://doi.org/10.1016/s0008-6363(02)00319-x

    Article  CAS  PubMed  Google Scholar 

  101. Semenza GL (1999) Perspectives on oxygen sensing. Cell 98:281–284. https://doi.org/10.1016/s0092-8674(00)81957-1

    Article  CAS  PubMed  Google Scholar 

  102. Shang L, Ananthakrishnan R, Li Q, Quadri N, Abdillahi M, Zhu Z, Qu W, Rosario R, Toure F, Yan SF, Schmidt AM, Ramasamy R (2010) RAGE modulates hypoxia/reoxygenation injury in adult murine cardiomyocytes via JNK and GSK-3beta signaling pathways. PLoS One 5:e10092. https://doi.org/10.1371/journal.pone.0010092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Sharma HS, Das DK (1997) Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm 6:175–183. https://doi.org/10.1080/09629359791668

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G (2015) Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res 117:279–288. https://doi.org/10.1161/CIRCRESAHA.117.306878

    Article  CAS  PubMed  Google Scholar 

  105. Skyschally A, Gres P, Hoffmann S, Haude M, Erbel R, Schulz R, Heusch G (2007) Bidirectional role of tumor necrosis factor-alpha in coronary microembolization: progressive contractile dysfunction versus delayed protection against infarction. Circ Res 100:140–146. https://doi.org/10.1161/01.RES.0000255031.15793.86

    Article  CAS  PubMed  Google Scholar 

  106. Thielmann M, Kottenberg E, Kleinbongard P, Wendt D, Gedik N, Pasa S, Price V, Tsagakis K, Neuhauser M, Peters J, Jakob H, Heusch G (2013) Cardioprotective and prognostic effects of remote ischaemic preconditioning in patients undergoing coronary artery bypass surgery: a single-centre randomised, double-blind, controlled trial. Lancet 382:597–604. https://doi.org/10.1016/S0140-6736(13)61450-6

    Article  PubMed  Google Scholar 

  107. Venugopal V, Hausenloy DJ, Ludman A, Di Salvo C, Kolvekar S, Yap J, Lawrence D, Bognolo J, Yellon DM (2009) Remote ischaemic preconditioning reduces myocardial injury in patients undergoing cardiac surgery with cold-blood cardioplegia: a randomised controlled trial. Heart 95:1567–1571. https://doi.org/10.1136/hrt.2008.155770

    Article  CAS  PubMed  Google Scholar 

  108. Wang L, Zhang TP, Zhang Y, Bi HL, Guan XM, Wang HX, Wang X, Du J, Xia YL, Li HH (2016) Protection against doxorubicin-induced myocardial dysfunction in mice by cardiac-specific expression of carboxyl terminus of hsp70-interacting protein. Sci Rep 6:28399. https://doi.org/10.1038/srep28399

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Wu H, Lei S, Yuan J, Liu X, Zhang D, Gu X, Zhang L, Xia Z (2013) Ischemic postconditioning downregulates Egr-1 expression and attenuates postischemic pulmonary inflammatory cytokine release and tissue injury in rats. J Surg Res 181:204–212. https://doi.org/10.1016/j.jss.2012.07.031

    Article  CAS  PubMed  Google Scholar 

  110. Wu J, Guo W, Lin SZ, Wang ZJ, Kan JT, Chen SY, Zhu YZ (2016) Gp130-mediated STAT3 activation by S-propargyl-cysteine, an endogenous hydrogen sulfide initiator, prevents doxorubicin-induced cardiotoxicity. Cell Death Dis 7:e2339. https://doi.org/10.1038/cddis.2016.209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wu Q, Wang T, Chen S, Zhou Q, Li H, Hu N, Feng Y, Dong N, Yao S, Xia Z (2018) Cardiac protective effects of remote ischaemic preconditioning in children undergoing tetralogy of fallot repair surgery: a randomized controlled trial. Eur Heart J 39:1028–1037. https://doi.org/10.1093/eurheartj/ehx030

    Article  CAS  PubMed  Google Scholar 

  112. Yadav SS, Howell DN, Gao W, Steeber DA, Harland RC, Clavien PA (1998) L-selectin and ICAM-1 mediate reperfusion injury and neutrophil adhesion in the warm ischemic mouse liver. Am J Physiol 275:G1341–G1352. https://doi.org/10.1152/ajpgi.1998.275.6.G1341

    Article  CAS  PubMed  Google Scholar 

  113. Yan SF, Fujita T, Lu J, Okada K, Shan Zou Y, Mackman N, Pinsky DJ, Stern DM (2000) Egr-1, a master switch coordinating upregulation of divergent gene families underlying ischemic stress. Nat Med 6:1355–1361. https://doi.org/10.1038/82168

    Article  CAS  PubMed  Google Scholar 

  114. Yellon DM, Hausenloy DJ (2007) Myocardial reperfusion injury. N Engl J Med 357:1121–1135. https://doi.org/10.1056/NEJMra071667

    Article  CAS  PubMed  Google Scholar 

  115. You L, Wang Z, Li H, Shou J, Jing Z, Xie J, Sui X, Pan H, Han W (2015) The role of STAT3 in autophagy. Autophagy 11:729–739. https://doi.org/10.1080/15548627.2015.1017192

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Zhai P, Eurell TE, Cotthaus R, Jeffery EH, Bahr JM, Gross DR (2000) Effect of estrogen on global myocardial ischemia-reperfusion injury in female rats. Am J Physiol Heart Circ Physiol 279:H2766–H2775. https://doi.org/10.1152/ajpheart.2000.279.6.H2766

    Article  CAS  PubMed  Google Scholar 

  117. Zhai P, Sadoshima J (2012) Glycogen synthase kinase-3beta controls autophagy during myocardial ischemia and reperfusion. Autophagy 8:138–139. https://doi.org/10.4161/auto.8.1.18314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhang T, Zhang Y, Cui M, Jin L, Wang Y, Lv F, Liu Y, Zheng W, Shang H, Zhang J, Zhang M, Wu H, Guo J, Zhang X, Hu X, Cao CM, Xiao RP (2016) CaMKII is a RIP3 substrate mediating ischemia- and oxidative stress-induced myocardial necroptosis. Nat Med 22:175–182. https://doi.org/10.1038/nm.4017

    Article  CAS  PubMed  Google Scholar 

  119. Zhao ZQ, Nakamura M, Wang NP, Velez DA, Hewan-Lowe KO, Guyton RA, Vinten-Johansen J (2000) Dynamic progression of contractile and endothelial dysfunction and infarct extension in the late phase of reperfusion. J Surg Res 94:133–144. https://doi.org/10.1006/jsre.2000.6029

    Article  CAS  PubMed  Google Scholar 

  120. Zhou C, Liu Y, Yao Y, Zhou S, Fang N, Wang W, Li L (2013) beta-blockers and volatile anesthetics may attenuate cardioprotection by remote preconditioning in adult cardiac surgery: a meta-analysis of 15 randomized trials. J Cardiothorac Vasc Anesth 27:305–311. https://doi.org/10.1053/j.jvca.2012.09.028

    Article  CAS  PubMed  Google Scholar 

  121. Zhou Y, Zhang Y, Gao F, Guo F, Wang J, Cai W, Chen Y, Zheng J, Shi G (2010) N-n-butyl haloperidol iodide protects cardiac microvascular endothelial cells from hypoxia/reoxygenation injury by down-regulating Egr-1 expression. Cell Physiol Biochem 26:839–848. https://doi.org/10.1159/000323993

    Article  CAS  PubMed  Google Scholar 

  122. Zhu H, Bunn HF (1999) Oxygen sensing and signaling: impact on the regulation of physiologically important genes. Respir Physiol 115:239–247

    Article  CAS  PubMed Central  Google Scholar 

  123. Zhu P, Hu S, Jin Q, Li D, Tian F, Toan S, Li Y, Zhou H, Chen Y (2018) Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: a mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol 16:157–168. https://doi.org/10.1016/j.redox.2018.02.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by Heart Research Australia. The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Author information

Authors and Affiliations

  1. Department of Cardiology, Kolling Institute, Northern Sydney Local Health District, Level 12, Royal North Shore Hospital, Cnr Reserve Rd and Westbourne, St Leonards, NSW, 2065, Australia

    M. Billah, A. Ridiandries, U. K. Allahwala, A. Dona & R. Bhindi

  2. Sydney Medical School Northern, University of Sydney, Sydney, NSW, 2006, Australia

    M. Billah, A. Ridiandries, U. K. Allahwala, A. Dona & R. Bhindi

  3. Vascular Biology and Translational Research, School of Medical Sciences, University of New South Wales, Sydney, Australia

    L. M. Khachigian

  4. Inflammation Group, Heart Research Institute, University of Sydney, Sydney, NSW, Australia

    B. S. Rayner

  5. School of Life Sciences, Independent University Bangladesh, Dhaka, Bangladesh

    M. Billah

Authors
  1. M. Billah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. A. Ridiandries
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. B. S. Rayner
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. K. Allahwala
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. A. Dona
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. M. Khachigian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. R. Bhindi
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors take responsibility for all aspects of the reliability and freedom of bias of the data presented and their discussed interpretation

Corresponding author

Correspondence to M. Billah.

Ethics declarations

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Billah, M., Ridiandries, A., Rayner, B.S. et al. Egr-1 functions as a master switch regulator of remote ischemic preconditioning-induced cardioprotection. Basic Res Cardiol 115, 3 (2020). https://doi.org/10.1007/s00395-019-0763-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s00395-019-0763-9

Keywords

Search

Navigation