title: 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.
abstract: BACKGROUND
  Egr-1 is implicated in the pathogenesis of myocardial ischemia-reperfusion injury. The aim of this study was to ascertain the effectiveness of intracoronary delivery of DNAzyme targeting the transcription factor Egr-1 at reperfusion following experimental myocardial ischemia.
  
  
  RESULTS
  Functional DNAzyme targeting Egr-1 or a size-matched scrambled control were delivered via the intracoronary route immediately on reperfusion after 60 minutes' balloon occlusion of the left anterior descending coronary artery in a pig model of myocardial I/R injury (n=7 per treatment group). Heart function and extent of myocardial infarction were determined following intervention by echocardiography and cardiac magnetic resonance imaging, respectively. Hearts were removed and examined for molecular and histological markers of inflammation and apoptosis. Administration of functional DNAzyme led to an overall decrease in the expression of inflammatory markers including intracellular adhesion molecule-1, tissue factor, and complement 3, with associated decreases in the extent of neutrophil infiltration, oxidative damage, and subsequent apoptosis within the infarct border zone. Functional significance was indicated by an increase in salvaged left ventricular myocardium (P=0.012), ejection fraction (P=0.002), and fractional area change (P=0.039) in the functional DNAzyme-treated group compared with the control.
  
  
  CONCLUSIONS
  Egr-1 silencing through intracoronary delivery of a targeting DNAzyme at the time of reperfusion following acute myocardial ischemia decreases myocardial inflammation and apoptosis leading to improved cardiac function.
authors.affiliation: North Shore Heart Research Group, Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Australia.
authors.forename: Benjamin S
authors.initials: BS
authors.lastname: Rayner
authors.forename: Gemma A
authors.initials: GA
authors.lastname: Figtree
authors.forename: Tharani
authors.initials: T
authors.lastname: Sabaretnam
authors.forename: Ping
authors.initials: P
authors.lastname: Shang
authors.forename: Jawad
authors.initials: J
authors.lastname: Mazhar
authors.forename: James C
authors.initials: JC
authors.lastname: Weaver
authors.forename: William N
authors.initials: WN
authors.lastname: Lay
authors.forename: Paul K
authors.initials: PK
authors.lastname: Witting
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Hunyor
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Grieve
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Ravinay
authors.initials: R
authors.lastname: Bhindi
mesh_terms: D000818:Animals; D017209:Apoptosis; D021881:DNA, Catalytic / Q000008:administration & dosage*; D004195:Disease Models, Animal; D015536:Down-Regulation; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D004452:Echocardiography; D018836:Inflammation Mediators / Q000378:metabolism; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D009203:Myocardial Infarction / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000175:diagnosis / Q000201:enzymology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D020556:Neutrophil Infiltration; D009841:Oligonucleotides / Q000008:administration & dosage*; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000378:metabolism; D013318:Stroke Volume; D013552:Swine; D013599:Systole; D013997:Time Factors; D018487:Ventricular Dysfunction, Left / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D016277:Ventricular Function, Left
chemical_list: D021881:DNA, Catalytic; D051766:Early Growth Response Protein 1; D018836:Inflammation Mediators; D009841:Oligonucleotides; D012333:RNA, Messenger
keywords: DNAzyme; Egr‐1; acute myocardial ischemia reperfusion
references.citation: FASEB J. 2001 Dec;15(14):2757-9
references.pmid: 11606484
references.citation: Nat Cell Biol. 2001 Dec;3(12):1124-8
references.pmid: 11781575
references.citation: J Am Coll Cardiol. 2005 Aug 2;46(3):536-41
references.pmid: 16053971
references.citation: Circ Res. 2006 Feb 3;98(2):186-91
references.pmid: 16456111
references.citation: Am J Pathol. 1996 Sep;149(3):953-61
references.pmid: 8780399
references.citation: J Cell Biochem. 2005 Jan 1;94(1):117-25
references.pmid: 15517593
references.citation: Cell Physiol Biochem. 2010;26(6):839-48
references.pmid: 21220915
references.citation: J Pathol. 2012 Jun;227(2):157-64
references.pmid: 22344601
references.citation: Ann Surg. 2009 Jun;249(6):889-99
references.pmid: 19474697
references.citation: J Cell Physiol. 2002 Dec;193(3):287-92
references.pmid: 12384981
references.citation: Biochem Biophys Res Commun. 2007 Jul 13;358(4):1120-7
references.pmid: 17521609
references.citation: J Mol Cell Cardiol. 2011 Mar;50(3):522-33
references.pmid: 21219908
references.citation: J Biol Chem. 2005 Nov 25;280(47):39394-402
references.pmid: 16172122
references.citation: J Immunol. 2005 Jul 1;175(1):541-6
references.pmid: 15972690
references.citation: Circulation. 1995 Nov 1;92(9):2676-82
references.pmid: 7586372
references.citation: J Biol Chem. 2008 May 2;283(18):12120-8
references.pmid: 18281687
references.citation: Nat Med. 2000 Dec;6(12):1355-61
references.pmid: 11100120
references.citation: J Cardiovasc Magn Reson. 2011 Sep 15;13:50
references.pmid: 21917186
references.citation: J Biol Chem. 1997 Aug 8;272(32):20131-8
references.pmid: 9242687
references.citation: J Clin Invest. 1997 Jun 1;99(11):2635-43
references.pmid: 9169493