Abstract 16987: Genetic Deletion of DJ-1/Park7 Increases Myocardial Ischemia/Reperfusion Injury

Abstract

Background: DJ-1/Park7 has classically been implicated in early onset Parkinson's disease, but has recently been identified to play a role in the cellular response to stress. For instance, in non-cardiac cells, DJ-1 has been shown to associate with and inactivate Daxx, a modulator of apoptosis. DJ-1 is expressed in the heart, but its role in mediating myocardial injury is currently unknown. Therefore, we examined how a deficiency in DJ-1 would affect 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 I followed by 24 hr of R, at which time the extent of myocardial injury was evaluated. The deficiency of DJ-1 significantly increased the extent of myocardial injury as evidenced by a 45% increase in myocardial infarct size relative to the area-at-risk (INF/AAR), a 44% increase in INF relative to the left ventricle (LV) and a 155% increase in circulating troponin-I levels. In an effort to evaluate the signaling mechanism responsible for the increased injury in DJ-1 KO mice, WT and KO animals were subjected to 45 min of I followed by 1 hr R. Western blot analysis revealed that DJ-1 KO mice exhibited a higher baseline cytosolic protein expression of Daxx compared to WT. Following MI/R, Daxx expression was increased in WT mice and this increase was further augmented by the absence of DJ-1. DJ-1 is known to prevent the association of Daxx with ASK-1, leading to a decrease in the pro-apoptotic phosphorylation of Jnk (Jnk-P). Further analysis revealed that DJ-1 KO mice displayed both higher levels of Jnk-P and cleaved caspase-3 after MI/R when compared to WT mice. Conclusions: These data suggest for the first time that DJ-1 plays a protective role in the heart following MI/R injury as evidenced by the increase in Daxx-mediated apoptosis and exacerbated myocardial injury observed in DJ-1 deficient mice.