Abstract 412: DJ-1 Deficiency Impairs Post-Ischemic Cardiac Fatty Acid Oxidation

Abstract

Background: DJ-1 is a cytoprotective protein implicated in many cellular processes. We have recently shown that DJ-1 plays a protective role in the setting of acute myocardial ischemia-reperfusion injury and heart failure. However, specific mechanisms of action remain unknown. Here, we sought to determine if DJ-1 maintains fatty acid oxidation following myocardial I/R injury via the regulation of PPARalpha transcriptional activity. Methods and Results: WT and DJ-1 KO hearts were subjected to 45 minutes of ischemia via coronary artery ligation followed by up to 72 hours of reperfusion. Initial studies revealed that PPARalpha activity (PPARalpha Transcription Factor Assay Kit; abcam) was lower in DJ-1 KO hearts under both basal (sham) and I/R conditions. Next, we performed an analysis of PPAR genes using a qPCR array (Mouse PPAR Targets RT2 Profiler PCR Array from Qiagen) that profiled the expression of 84 key genes involved in PPAR activation and response. Marked differences in genes involved in FA metabolism were evident in the hearts of DJ-1 KO mice. Further studies using qPCR validated a significant decrease in the expression of acsl1 (protein ACSL1), acsl3, acsl5, cpt1b (protein CPT1), slc25a20 (protein CACT), and cpt2. The protein expression of ACSL1, CPT1, and CACT were also decreased in the hearts of DJ-1 KO mice following I/R injury. These changes were accompanied by higher cardiac lipid content and depressed mitochondrial fatty-acid β-oxidation and ATP synthesis. Conclusion: These data demonstrate that DJ-1 plays an essential role in regulating post-I/R cardiac FAO. Future studies will garner mechanistic insight for the impaired function of PPARalpha with the loss of DJ-1.