Novel Insights into Ischemic-Induced Cardiac Remodeling

点击翻译按钮获取中文摘要

Project Summary DJ-1 is a cytoprotective protein that is activated by oxidative stress. Due in large part to the association of DJ-1 with Parkinson's Disease, most studies aimed at investigating its role in response to pathological stimuli have been confined to the brain or neuronal cells. However, DJ-1 is expressed in the heart where it also possesses cytoprotective actions. Studies indicate that DJ-1 plays an important role in multiple cellular processes, including oxidative stress response, anti-apoptotic signaling, and transcriptional regulation. However, the cellular mechanisms underlying these reported actions remain largely unknown. Given that DJ-1 is a small, dimeric, single-domain protein, it either possesses multiple functions to account for these actions or there is a single biochemical activity that explains all of them. What is known is that DJ-1 is activated by the removal of a 15-amino acid peptide at its C terminus in response to oxidative stress. We recently provided the first evidence that DJ-1 is activated within hours following the onset of acute myocardial ischemia-reperfusion (I/R). Preliminary studies from our lab demonstrate that cardiac DJ-1 remains active for up to 7 days following the onset of ischemic injury. Furthermore, our studies revealed that DJ-1 deficient mice displayed worse cardiac dysfunction in response to ischemic-induced heart failure compared to wild-type mice. Elevated levels of hypertrophy, fibrosis, and inflammation accompanied the worse cardiac dysfunction in the DJ-1 deficient mice. More importantly, we provide novel evidence that the delivery of the active form of DJ-1 using recombinant adeno-associated virus 9 (AAV9-DJ1WTΔC) reduces the development of ischemic-induced heart failure. This is the first and only demonstration that an active form of DJ-1 provides cytoprotection in an in vivo model of injury. In this proposal, we will expand on our previous findings and attempt to fill knowledge gaps in the literature regarding the cellular actions of DJ-1. 3 specific aims have been proposed. Aim 1 will determine if DJ- 1 is a novel cardiac deglycase that opposes glycative stress. Aim 2 will determine if DJ-1 attenuates ischemic- induced heart failure by promoting the cardioprotective actions of thioredoxin. Aim 3 will determine if DJ-1 opposes TGF-β signaling by regulating the cardiac expression of Arkadia.