Abstract 19837: DJ-1/Park7 Protects the Heart Against Ischemia-reperfusion Injury Through the Modulation of SUMOylation (Best of Basic Science Abstract)
Background: DJ-1/Park7 is a ubiquitously expressed protein typically 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 aimed to examine the underlying molecular mechanisms mediating the actions of DJ-1 in the heart following the onset of myocardial ischemia-reperfusion (I/R) injury.
Methods and Results: Wild-type (WT) control and DJ-1 deficient (DJ-1 KO) mice were subjected to in vivo myocardial I/R injury. DJ-1 KO mice (n=9) displayed increased areas of infarction (%INF/LV or AAR: 30.2 vs 22.0%, 53.6 vs 39.0%, Troponin-I: 47.4 vs 19.9ng/ml, p<0.05 respectively) and worsened left ventricular function (LVEF: 43.7 vs 58.1%, p<0.001) when compared to WT mice (n=9), confirming a protective role for DJ-1 in the heart. In an effort to evaluate the potential mechanism(s) responsible for the increased injury in DJ-1 KO mice, we focused on SUMOylation, a post-translational modification process which regulates various aspects of protein function, including transcription, subcellular localization, DNA repair, and cell cycle. DJ-1 KO hearts after I/R injury were found to display enhanced accumulation of SUMO-1 modified proteins, (this modification is generally associated with cell injury), and reduced SUMO-2/3 modified proteins (this modification is generally associated with cytoprotection). Further analysis, revealed that the protein expression of the de-SUMOylation enzyme SENP-1 (removes SUMO-1 modifications) was reduced, whereas the expression of SENP-5 (removes SUMO-2/3 modifications) was enhanced in DJ-1 KO hearts after I/R injury. Changes in mRNA levels did not account for the altered protein expression of SENP-1 and SENP-5. So, we evaluated the direct interaction of DJ-1 with both proteins in hearts of WT mice following I/R using co-immunoprecipitation. We found that SENP1 binding with DJ-1 was down-regulated, whereas SENP5 binding with DJ-1 was up-regulated.
Conclusion: Our data demonstrated that the activation of DJ-1 in response to myocardial I/R injury protects the heart by the modulation of SUMOylation via direct binding of SENP1 and SENP5.
Author Disclosures: Y. Shimizu: None. L. Barr: None. T. Fields: None. J.W. Calvert: None.
- © 2015 by American Heart Association, Inc.