Myocardial salvage via coordinated induction of endogenous cardiac antioxidants

描述（由申请人提供）：心血管疾病（CVD）仍然是美国的主要死亡原因。大量的证据支持氧化应激在各种形式的CVD，特别是心肌缺血-再灌注损伤中的因果作用。因此，外源性抗氧化剂化合物已用于CVD的干预。然而，使用外源性抗氧化剂（包括维生素E）治疗CVD的临床试验得出了令人失望的结论。越来越多的人认识到，各种内源性抗氧化酶的协调作用对于ROS和其他介导心脏损伤的活性物质的有效解毒至关重要。因此，我们提出了一种新的策略，从心肌缺血-再灌注损伤的挽救心肌通过增强内源性抗氧化网络的协调表达。该项目的长期目标是开发一种高效的内源性抗氧化剂基心脏保护策略，以预防和/或延缓心脏疾病的氧化变性过程。这种心肌挽救策略依赖于对心脏抗氧化网络组成型和诱导型表达的分子调控的深刻理解。最近，发现Nrf 2是动物组织（包括肝脏和肺）中细胞保护基因表达的中心调节因子。然而，Nrf 2在调节心肌抗氧化网络中的作用仍有待确定。我们假设Nrf 2是调节心肌中抗氧化酶的协调表达所不可或缺的，并且Nrf 2调节的心脏抗氧化网络是从缺血-再灌注损伤中挽救心肌的新途径。因此，该R21提案旨在通过使用新的Nrf 2敲除小鼠模型来确定Nrf 2在调节心肌抗氧化剂的协调表达和所涉及的信号通路中的重要作用。有效的化学保护剂，3 H-1，2-二硫杂环戊烯-3-酮（D3 T）将被用来确定Nrf 2在调节心肌抗氧化剂的诱导表达和潜在机制中的中心作用。该提议还旨在确定心脏抗氧化剂的Nrf 2依赖性协调表达是否是体内缺血-再灌注损伤心肌挽救的关键机制。该项目的完成将确定Nrf 2信号传导作为减轻心肌缺血-再灌注损伤的新途径，并通过靶向Nrf 2调节的心肌抗氧化网络，为开发高效的心脏保护策略做出重要贡献。公共卫生相关性：心肌缺血再灌注损伤是临床上的一个主要问题，目前尚无有效的干预方法。大量证据支持活性氧（ROS）在心肌缺血再灌注损伤的发病机制中的因果作用。本项目旨在确定Nrf 2信号通路作为缺血再灌注损伤心肌挽救的新途径。该项目的完成将有助于开发一种高效的心脏保护策略，通过靶向Nrf 2调节的抗氧化网络来干预心肌缺血-再灌注损伤以及涉及ROS介导机制的其他心脏疾病。

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains the leading cause of death in the United States. A large body of evidence supports a causal role for oxidative stress in various forms of CVD, especially myocardial ischemia- reperfusion injury. As such, exogenous antioxidant compounds have been used for intervention of CVD. However, clinical trials on use of exogenous antioxidants, including vitamin E in management of CVD have reached disappointing conclusions. It is increasingly recognized that the coordinated actions of various endogenous antioxidant enzymes are essential for efficient detoxification of ROS and other reactive species that mediate cardiac injury. Accordingly, we propose a novel strategy for myocardial salvage from ischemia- reperfusion injury via enhancing the coordinated expression of the endogenous antioxidant network in myocardium. The long-term objective of this project is to develop a highly effective endogenous antioxidant- based cardioprotective strategy to prevent and/or retard the oxidative degenerative processes underlying cardiac disease. Such a strategy of myocardial salvage relies on a profound understanding of molecular regulation of constitutive and inducible expression of cardiac antioxidant network. Recently, Nrf2 is found to be a central regulator of cytoprotective gene expression in animal tissues, including liver and lung. However, the role of Nrf2 in regulating antioxidant network in myocardium remains to be determined. We hypothesize that Nrf2 is indispensable for regulating coordinated expression of antioxidant enzymes in myocardium, and that the Nrf2-regulated cardiac antioxidant network is a novel pathway for myocardial salvage from ischemia- reperfusion injury. Accordingly, this R21 proposal aims to identify the essential role of Nrf2 in regulating coordinated expression of myocardial antioxidants and the signaling pathways involved via using the novel Nrf2-knockout mouse model. The potent chemoprotective agent, 3H-1,2-dithiole-3-thione (D3T) will be used to define the central role of Nrf2 in regulating the inducible expression of myocardial antioxidants and the underlying mechanisms. This proposal will also be aimed to determine if Nrf2-dependent coordinated expression of cardiac antioxidants is a crucial mechanism for myocardial salvage from in vivo ischemia- reperfusion injury. Completion of this project will identify Nrf2 signaling as a novel pathway for mitigating myocardial ischemia-reperfusion injury, and significantly contribute to the development of a highly effective cardioprotective strategy via targeting on Nrf2-regulated antioxidant network in myocardium. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Myocardial ischemia-reperfusion injury is a major clinical problem, for which there is no effective approach to intervention. Substantial evidence supports a causal role for reactive oxygen species (ROS) in the pathogenesis of myocardial ischemia-reperfusion injury. This project aims to identify Nrf2 signaling as a novel pathway for myocardial salvage from ischemia-reperfusion injury. Completion of this project will contribute to the development of a highly effective cardioprotective strategy via targeting on Nrf2-regulated antioxidant network for intervention of myocardial ischemia-reperfusion injury as well as other cardiac disorders that involve an ROS-mediated mechanism.