Abstract 224: Cleavage of DNA Generated During Myocardial Ischemia/Reperfusion Protects the Heart from Injury

Abstract

Introduction: Neutrophils play a major role in early response to myocardial ischemia/reperfusion (MI/R) injury. During inflammation, neutrophils may form a meshwork of DNA fibers known as neutrophil extracellular traps (NETs). NETs are injurious to tissues and pro-thrombotic. It has been shown that DNase 1, which cleaves DNA, can disassemble NETs-induced thrombi in a flow chamber and reduce incidence of deep vein thrombosis in vivo in mice. Objective and Methods: To investigate the effect of DNase 1 on MI/R injury, we used a “closed chest” mouse model of acute myocardial infarction for 60 min, followed by 24 h reperfusion. Mice were treated with DNase 1 or vehicle immediately after reperfusion. Results: Mice receiving DNase 1 developed a significantly smaller infarcted area compared to mice treated with vehicle (buffer). Immunohistochemical analysis of the myocardium revealed infiltrated neutrophils positive for Gr-1 and citrulinated histones (citH3). Also, extracellular citH3, an element and marker of NETs formation, was observed in an infarcted area mainly in mice treated with vehicle. Of interest, MI/R caused an increase in circulating nucleosomes and DNase 1 treatment revealed a significant decrease in plasma nucleosome levels, as compared with vehicle-treated mice, 24 h after MI/R. Conclusions: We show that DNase 1 reduced MI/R infarct size in mice and the lesser injury was confirmed by histological analysis. MI/R resulted in the presence of extracellular citH3, most likely originating from neutrophils, in myocardial sections of vehicle-treated MI/R mice but less so in mice receiving DNase 1. We also observed a decrease in nucleosomes in plasma from MI/R mice treated with DNase 1. Our results support a protective role for DNase 1 in MI/R.