title: Intracoronary delivery of DNAzymes targeting human EGR-1 reduces infarct size following myocardial ischaemia reperfusion.
abstract: Despite improvements in treatment, myocardial infarction (MI) remains an important cause of morbidity and mortality. Inflammation arising from ischaemic and reperfusion injury is a key mechanism which underpins myocardial damage and impairment of cardiac function. Early growth response-1 (Egr-1) is an early immediate gene and a master regulator that has been implicated in the pathogenesis of ischaemia-reperfusion (IR) injury. This study sought to examine the effect of selective inhibition of Egr-1 using catalytic deoxyribonucleic acid molecules (DNAzymes, DZs) delivered via the clinically relevant coronary route in a large animal model of myocardial IR. It was hypothesized that Egr-1 inhibition with intracoronary DZ would reduce infarction size by modulating its downstream effector molecules. Egr-1 DZs inhibited the adherence of THP-1 monocytes to IL-1β-activated endothelial cells in vitro and retained its catalytic activity up to 225 min after in vivo administration. In a porcine model of myocardial IR (45 min ischaemia/3 h reperfusion), DZ was taken up in the cytoplasm and nuclei of cardiomyocytes and endothelial cells in the myocardium after intracoronary delivery. Egr-1 DZs reduced infarct size and improved cardiac functional recovery following intracoronary delivery at the initiation of IR in this large animal model of MI. This was associated with inhibition of pro-inflammatory Egr-1 and ICAM-1 expression, and the reduced expression of TNF-α, PAI-1, TF, and myocardial MPO activity in tissue derived from the border zone of the infarct. Taken together, these data suggest that strategies targeting Egr-1 via the intracoronary route after IR injury in pigs have potential therapeutic implications in human MI.
authors.affiliation: Centre for Vascular Research, University of New South Wales, Sydney, NSW 2052, Australia. ravinay.bhindi@sydney.edu.au
authors.forename: Ravinay
authors.initials: R
authors.lastname: Bhindi
authors.forename: Roger G
authors.initials: RG
authors.lastname: Fahmy
authors.forename: Aisling C
authors.initials: AC
authors.lastname: McMahon
authors.forename: Levon M
authors.initials: LM
authors.lastname: Khachigian
authors.forename: Harry C
authors.initials: HC
authors.lastname: Lowe
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002478:Cells, Cultured; D004277:DNA, Single-Stranded / Q000008:administration & dosage*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics* / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007267:Injections; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009000:Monocytes / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009195:Peroxidase / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D020127:Recovery of Function; D013552:Swine; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C400152:DNA enzyme ED5; D004277:DNA, Single-Stranded; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D053583:Interleukin-1beta; D017395:Plasminogen Activator Inhibitor 1; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D013925:Thromboplastin; D009195:Peroxidase