Novel Insights into Ischemic-Induced Cardiac Remodeling

项目摘要 DJ-1是一种细胞保护蛋白，可被氧化应激激活。在很大程度上是由于DJ-1的联合 对于帕金森氏症，大多数旨在研究其在病理刺激反应中的作用的研究都 仅限于大脑或神经细胞。然而，DJ-1在心脏中表达，在那里它也拥有 细胞保护作用。研究表明，DJ-1在多种细胞过程中发挥重要作用， 包括氧化应激反应、抗凋亡信号和转录调控。然而， 这些已报道的作用背后的细胞机制在很大程度上仍不清楚。鉴于DJ-1是一种小型的， 二聚体，单域蛋白，它要么具有多种功能来解释这些作用，要么有一个 可以解释所有这些的单一生化活动。已知的是，DJ-1是通过移除 C末端有15个氨基酸的多肽对氧化应激的反应。我们最近提供了第一个证据 DJ-1在急性心肌缺血-再灌注(I/R)后数小时内被激活。 我们实验室的初步研究表明，心脏DJ-1在心脏移植后7天内保持活跃 缺血性损伤的发病。此外，我们的研究表明，DJ-1缺陷小鼠的心脏表现更差 与野生型小鼠相比，缺血型心力衰竭小鼠的功能障碍。高水平的 在DJ-1缺陷小鼠中，肥大、纤维化和炎症伴随着更严重的心功能障碍。 更重要的是，我们提供了新的证据表明，使用重组人DJ-1的活性形式传递 腺相关病毒9(AAV9-DJ1WTΔC)可减少缺血性心力衰竭的发生。这 是第一个也是唯一一个证明DJ-1的活性形式在活体模型中提供细胞保护的证据 受伤。在这项提案中，我们将扩展我们以前的发现，并试图填补 有关DJ-1细胞作用的文献。提出了三个具体目标。目标一号将决定DJ是否- 1是一种新的抗糖化应激的心脏变性病例。AIM 2将确定DJ-1是否减轻缺血- 通过促进硫氧还蛋白的心脏保护作用诱导心力衰竭。AIM 3将确定DJ-1是否 通过调节Arkadia的心脏表达来反对转化生长因子-β信号转导。

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.