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

基本信息

批准号：
8197419
负责人：
John Winter Calvert
金额：
$ 38.36万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
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/8197419
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

项目摘要

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）：心力衰竭是指心脏无法满足血流动力学需求，代表各种形式的心血管疾病的末期。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）已被证明在各种体外和体内心脏损伤模型中具有心脏保护作用。尽管先前已记录了 H2S 在急性缺血再灌注损伤模型中的生理和心脏保护作用，但介导这些作用的信号机制尚未得到充分研究。此外，H2S 的信号传导机制主要在体外模型系统中进行研究，很少有研究真正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极其重要且及时。该提案的总体目标是评估在心力衰竭情况下观察到的 H2S 治疗心脏保护作用的信号传导机制。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，本研究的中心假设是 H2S 上调内源性抗氧化剂，减轻线粒体功能障碍，并以 Nrf2 依赖性方式减少肥大。为了检验这一假设，提出了 3 个具体目标。具体目标 1 将评估 Nrf2 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 Nrf2/Trx1 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 Nrf2 依赖性信号传导诱导线粒体生物发生。拟议的研究将显着推进我们目前对心力衰竭发生机制的理解，并将回答有关心力衰竭情况下 H2S 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开发治疗心力衰竭的 H2S 疗法奠定基础。公共卫生相关性：尽管医疗保健取得了巨大进步，但心血管疾病仍然是美国的头号杀手，而心血管疾病直接导致的心力衰竭影响着美国近 530 万人，导致约 348 亿美元的支出一年来支付相关的医疗保健相关费用。拟议的研究将评估释放硫化氢的化合物在临床相关且高度转化的心力衰竭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，并将回答有关心力衰竭中硫化氢心脏保护作用的信号传导机制的重要问题。