Abstract 333: Deficiency of DJ-1 Leads to Increased Injury following Myocardial Ischemia by Enhancing Apoptosis and Oxidative Stress

Abstract

Background: DJ-1 is a ubiquitously expressed protein that has typically been associated with the development of early onset Parkinson’s disease. Recent data suggests that it also plays a role in the cellular response to stress. Although much is known about DJ-1 in the brain, very little has been investigated in the heart. Here, we tested the hypothesis that a deficiency in DJ-1 would enhance myocardial ischemia-reperfusion (MI/R) injury. Methods and Results: Wild-type (WT) control and DJ-1 knockout (DJ-1 KO) mice were subjected to 45 min of left coronary artery ischemia followed by 24 hrs of reperfusion. The deficiency of DJ-1 significantly increased myocardial infarct size relative to both the area-at-risk and entire left ventricle, as well as increased circulating troponin-I levels (Panels A-B). Echocardiography and hemodynamic analysis at 1 week of reperfusion revealed that DJ-1 KO mice experienced greater left ventricular dilatation and hypertrophy, displayed exacerbated left ventricular dysfunction, and displayed worse contractility and relaxation when compared to WT controls. In an effort to evaluate the signaling mechanism responsible for the increased injury in DJ-1 KO mice, additional WT and KO animals were subjected to 45 min of ischemia followed by 4 hrs of reperfusion. DJ-1 KO hearts were found to display higher levels of oxidative stress, greater caspase-3 activity (Panel C), enhanced phosphorylation of Jnk, and enhanced activation of the mitochondrial fission protein, dynamin-related protein 1 (Drp1). Conclusions: These findings provide important information that DJ-1 plays a protective role in heart against acute MI/R injury.