Hydrogen sulfide attenuates heart failure through Nrf2-mediated signaling

硫化氢通过 Nrf2 介导的信号传导减轻心力衰竭

• 批准号: 8011451
• 负责人: John Winter Calvert
• 金额: $ 38.75万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-04 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8011451
• 关键词: Acute; Address; Affect; Antioxidants; Apoptosis; Attenuated; Biogenesis; Biological Models; Cardiac; Cardiovascular Diseases; Cardiovascular system; Caring; Cystathionine; Developed Countries; Development; Enzymes; Experimental Models; Foundations; Functional disorder; Health; Healthcare; Heart; Heart Hypertrophy; Heart failure; Histone Deacetylase; Homeostasis; Hydrogen Sulfide; Hypertrophy; In Vitro; Incidence; Injury; Ischemia; Lyase; Mediating; Mitochondria; Modeling; Mus; Myocardial Infarction; Myocardial Ischemia; Myocardium; Nuclear; Oxidative Stress; Pharmacotherapy; Physiological; Play; Prevalence; Regulation; Reperfusion Injury; Reperfusion Therapy; Role; Signal Transduction; Signaling Molecule; Staging; System; Testing; Therapeutic; Thioredoxin; United States; Up-Regulation; Work; clinically relevant; cost; design; heme oxygenase-1; hemodynamics; improved; in vitro Model; in vivo; in vivo Model; meetings; mitochondrial dysfunction; novel; nuclear respiratory factor; pressure; protective effect; protein complex; protein expression; public health relevance; therapy design; transcription factor

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. PUBLIC HEALTH RELEVANCE: Despite numerous advances in health care, cardiovascular disease remains the number one killer in the United States and heart failure, as a direct result of cardiovascular disease, affects nearly 5.3 million people in the United States resulting in about $34.8 billion being spent a year to cover associated health care related costs. The proposed studies will evaluate the efficacy of a hydrogen sulfide releasing compound in clinically relevant and highly translational experimental model systems of heart failure. 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 hydrogen sulfide in the setting of heart failure.

描述（由申请人提供）：心力衰竭是心脏无法满足血流动力学需求，代表各种形式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增加。据估计，美国有570万人患有心力衰竭，导致每年花费约372亿美元来支付相关的医疗保健相关费用。因此，需要设计与标准护理手段一致的药物治疗，以减少导致心力衰竭发展的损伤程度。最近，硫化氢（H2S）已被证明是心脏保护在各种体外和体内模型的心脏损伤。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先前已被记录，但介导这些作用的信号传导机制尚未被充分研究。此外，归因于H2S的信号传导机制主要在体外模型系统中进行了研究，很少有研究实际探索体内系统的保护作用。此外，尚未研究H2S在心力衰竭情况下的心脏保护作用。因此，本申请中提出的研究非常重要和及时。本提案的总体目的是评估H2S治疗在心力衰竭背景下观察到的心脏保护作用的信号传导机制。为此，转录因子Nrf 2已被确定为这些心脏保护作用的可能调节因子。因此，拟议研究的中心假设是H2S上调内源性抗氧化剂，减轻线粒体功能障碍，并以Nrf 2依赖性方式减少肥大。为了验证这一假设，提出了三个具体目标。具体目标1将评估Nrf 2信号传导在介导H2S抗氧化作用中的作用。具体目标2将研究H2S是否通过Nrf 2/Trx 1依赖性信号传导抑制细胞凋亡和心脏肥大。具体目标3将研究H2S是否通过Nrf 2依赖性信号传导诱导线粒体生物合成。拟议的研究将显着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传导机制的重要问题。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。 公共卫生相关性：尽管在医疗保健方面取得了许多进步，但心血管疾病仍然是美国的头号杀手，并且作为心血管疾病的直接结果的心力衰竭影响了美国近530万人，导致每年花费约348亿美元来支付相关的医疗保健相关费用。拟议的研究将评估硫化氢释放化合物在心力衰竭的临床相关和高度转化的实验模型系统中的功效。拟议的研究将显着推进我们目前对心力衰竭发展机制的理解，并将回答有关在心力衰竭背景下硫化氢心脏保护作用的信号传导机制的重要问题。