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 DNA zyme targeting the transcription factor Egr‐1 at reperfusion following experimental myocardial ischemia. Methods and Results Functional DNA zyme 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 DNA zyme 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 DNA zyme–treated group compared with the control. Conclusions Egr‐1 silencing through intracoronary delivery of a targeting DNA zyme at the time of reperfusion following acute myocardial ischemia decreases myocardial inflammation and apoptosis leading to improved cardiac function.