Myocardial salvage via coordinated induction of endogenous cardiac antioxidants

描述（由申请人提供）：心血管疾病（CVD）仍然是美国死亡的主要原因。大量证据支持氧化应激在各种形式的心血管疾病，特别是心肌缺血-再灌注损伤中的因果作用。因此，外源性抗氧化化合物已被用于心血管疾病的干预。然而，使用外源性抗氧化剂（包括维生素E）治疗心血管疾病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同作用对于活性氧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，我们提出了一种通过增强心肌内源性抗氧化网络的协调表达来挽救缺血-再灌注损伤心肌的新策略。该项目的长期目标是开发一种高效的内源性抗氧化剂心脏保护策略，以预防和/或延缓心脏疾病的氧化退行性过程。这种挽救心肌的策略依赖于对心脏抗氧化网络组成和诱导表达的分子调控的深刻理解。最近，Nrf2被发现是动物组织（包括肝和肺）中细胞保护基因表达的中心调节因子。然而，Nrf2在调节心肌抗氧化网络中的作用尚不明确。我们推测Nrf2在调节心肌中抗氧化酶的协调表达中是必不可少的，并且Nrf2调控的心脏抗氧化网络是缺血再灌注损伤心肌修复的新途径。因此，本R21提案旨在通过使用新型Nrf2敲除小鼠模型，确定Nrf2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。强效化学保护剂3h -1,2-二硫基-3-硫酮（D3T）将用于确定Nrf2在调节心肌抗氧化剂诱导表达中的核心作用及其潜在机制。该研究还旨在确定nrf2依赖性心脏抗氧化剂的协调表达是否是体内缺血-再灌注损伤中心肌恢复的关键机制。该项目的完成将确定Nrf2信号作为减轻心肌缺血-再灌注损伤的新途径，并通过靶向Nrf2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大贡献。心肌缺血再灌注损伤是一个重要的临床问题，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发病机制中的因果作用。本项目旨在确定Nrf2信号作为缺血-再灌注损伤心肌修复的新途径。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nrf2调节的抗氧化网络来干预心肌缺血-再灌注损伤以及其他涉及ros介导机制的心脏疾病。

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.