Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling

描述（由申请人提供）：心力衰竭是指心脏不能满足血液动力学需求，是各种心血管疾病的终末期。在工业化国家，心力衰竭是一个主要的健康问题，其患病率和发病率一直在上升。据估计，美国有570万人患有心力衰竭，导致每年花费约372亿美元用于支付相关的医疗保健费用。因此，需要设计与标准护理手段相一致的药物治疗，以减少导致心力衰竭发展的损伤程度。最近，硫化氢（H2S）在各种体外和体内心脏损伤模型中被证明具有心脏保护作用。虽然H2S在急性缺血-再灌注损伤模型中的生理和心脏保护作用已经有文献记载，但介导这些作用的信号机制尚未得到充分研究。此外，归因于H2S的信号机制主要是在体外模型系统中研究的，很少有研究真正探索其在体内系统中的保护作用。此外，H2S在心力衰竭情况下的心脏保护作用尚未被研究。因此，在该应用中提出的研究是非常重要和及时的。本提案的总体目的是评估H2S治疗在心力衰竭中观察到的心脏保护作用的信号机制。为此，转录因子Nrf2已被确定为这些心脏保护作用的可能调节因子。因此，这些研究的中心假设是H2S上调内源性抗氧化剂，减轻线粒体功能障碍，并以nrf2依赖的方式减少肥大。为了验证这一假设，提出了3个具体目标。特异性目的1将评估Nrf2信号在介导H2S抗氧化作用中的作用。特异性目的2将研究H2S是否通过Nrf2/Trx1依赖信号抑制细胞凋亡和心脏肥厚。特异性目的3将研究H2S是否通过Nrf2依赖信号诱导线粒体生物发生。拟议的研究将显著推进我们目前对心力衰竭发展机制的理解，并将回答有关H2S在心力衰竭环境中心脏保护作用的信号机制的重要问题。此外，从这些研究中获得的信息将为H2S治疗心力衰竭的发展提供基础。

DESCRIPTION (provided by applicant): Heart failure is the inability of the heart to meet hemodynamic demands and represents the end stage of various forms of cardiovascular disease. In industrialized nations, heart failure represents a major health problem that has been increasing in prevalence and incidence. It is estimated that 5.7 million people in the United States have heart failure resulting in about $37.2 billion being spent a year to cover associated health care related costs. Therefore, drug therapy designed to coincide with the standard means of care are needed to decrease the extent of injury leading to the development of heart failure. Recently, hydrogen sulfide (H2S) has been shown to be cardioprotective in various in vitro and in vivo models of cardiac injury. Although the physiological and cardioprotective effects of H2S in acute models of ischemia- reperfusion injury have previously been documented, the signaling mechanisms that mediate these effects have not been fully studied. Moreover, the signaling mechanisms that have been attributed to H2S have predominantly been studied in in vitro model systems, with very few studies actually exploring the protective effects in in vivo systems. Additionally, the cardioprotective effects of H2S in the setting of heart failure have not been investigated. For this reason, the studies proposed in this application are extremely important and timely. The overall aim of this proposal is to evaluate the signaling mechanisms responsible for the observed cardioprotective effects of H2S therapy in the setting of heart failure. To this end, the transcription factor, Nrf2, has been identified as a possible regulator of these cardioprotective effects. Therefore, the central hypothesis for the proposed studies is that H2S up-regulates endogenous antioxidants, alleviates mitochondrial dysfunction, and reduces hypertrophy in a Nrf2-dependent manner. To test this hypothesis, 3 Specific Aims have been proposed. Specific Aim 1 will evaluate the role of Nrf2 signaling in mediating the antioxidant effects of H2S. Specific Aim 2 will investigate if H2S suppresses apoptosis and cardiac hypertrophy via Nrf2/Trx1- dependent signaling. Specific Aim 3 will investigate if H2S induces mitochondrial biogenesis via Nrf2- dependent signaling. The proposed studies will significantly advance our current understanding of the mechanisms responsible for the development of heart failure and will answer important questions regarding the signaling mechanism responsible for the cardioprotective effects of H2S in the setting of heart failure. Additionally, information gained from these studies will provide the foundation for the development of H2S therapy for the treatment of heart failure.