Hydrogen Sulfide for Prevention and Treatment of Ischemic Heart Failure

硫化氢预防和治疗缺血性心力衰竭

• 批准号: 9159965
• 负责人: Fadi N Salloum
• 金额: $ 38.13万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9159965
• 关键词: Acute; Acute myocardial infarction; Anti-Inflammatory Agents; Anti-inflammatory; Antiviral Agents; Apoptosis; Apoptotic; Attenuated; Blood flow; CASP1 gene; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cause of Death; Cessation of life; Chronic; Cicatrix; Clinical; Coronary Artery Ischemia; Cyclic GMP-Dependent Protein Kinases; Cystathionine; Data; Dose; Evolution; Functional disorder; Gases; Generations; Guanylate Cyclase; Heart; Heart Transplantation; Heart failure; Hydrogen Sulfide; Infarction; Inflammation; Inflammatory; Injury; Ischemia; Knockout Mice; Knowledge; Laboratories; Lead; Ligation; Lyase; Mediating; Metabolism; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Molecular Profiling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide; Obstruction; Organ; Oxidative Stress; Patients; Phosphorylation; Physiological; Prevention; Process; Production; Property; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Saline; Signal Transduction; Signaling Protein; Staging; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translating; attenuation; base; biological systems; cardiovascular health; cell injury; cofilin 2; design; gene therapy; improved; improved functioning; inhibitor/antagonist; innovation; interest; ischemic cardiomyopathy; novel; overexpression; phosphodiesterase V; prevent; protective effect; protein expression; sodium sulfide; stressor; tadalafil

Project Summary Hydrogen sulfide (H2S) is a powerful gasotransmitter, which has been shown to possess robust protective effects against ischemia-related injuries in the heart and other organs. Recent innovative studies by the PI and colleagues have identified regulation of endogenous levels of H2S to mediate the cardioprotective effect of phosphodiesterase-5 inhibitor, tadalafil, as well as a potent nitric oxide (NO)-independent guanylate cyclase activator, Cinaciguat, in the mouse heart. More recent studies from the PI's laboratory demonstrated the infarct-sparing and anti-inflammatory benefits of exogenous H2S against ischemia/reperfusion (I/R) injury as well as the role of cystathionine-γ-lyase-driven H2S generation in mediating the cardioprotective effects of gene therapy with protein kinase G. The purpose of this application is to further investigate the novel mechanisms by which H2S attenuates ischemic cardiomyopathy and inflammasome-mediated adverse remodeling in the failing heart. We will test the following hypotheses: 1) To investigate the protective effects of H2S on prevention of adverse remodeling post myocardial infarction (MI) and mitigation of ischemic heart failure. We will study the impact of H2S on LV scar size, function and remodeling. 2) To determine the chronic anti- inflammatory effect of H2S through suppression of NLRP3-inflammasome and the evolution of ischemic cardiomyopathy. 3) To study the role of H2S in attenuation of mitochondrial damage and propagation of inflammatory injury following MI by preserving MAVS and suppressing cofilin-2. These studies will be the first to demonstrate the protective effects of H2S for prevention of adverse remodeling following MI and also its potential therapeutic utility in the failing heart, possibly through attenuation of inflammasome-mediated maladaptive signaling. This is especially novel and the results will have a tremendous impact on further endorsing H2S as a potent therapeutic agent for ischemic heart failure. Moreover, these studies will provide novel mechanistic information by which new synthetic pharmacological agents with precisely controlled H2S release lead to improvement in overall cardiovascular health.

项目摘要 硫化氢（H2S）是一种强大的固定剂，已证明具有强大的保护性 针对心脏和其他器官缺血相关损伤的影响。 PI和 同事们已经确定了内源水平H2的调节，以介导 磷酸二酯酶5抑制剂，他达拉非以及潜在的一氧化氮（NO）非依赖性鸟苷酸环菌 激活剂，cinaciguat，在小鼠心脏中。 PI实验室的最新研究表明 外源性H2s梗死和抗炎的益处和抗缺血/再灌注（I/R）损伤 以及胱淀粉 - γ-裂解酶驱动的H2S在介导基因的心脏保护作用中的作用 蛋白激酶G的治疗。该应用的目的是进一步研究新机制 H2会减弱缺血性心肌病和炎性介导的不良重塑 心。我们将测试以下假设：1）研究H2S对预防的受保护作用 心肌梗塞后不良重塑（MI）和缺血性心力衰竭的缓解。我们将 研究H2S对LV疤痕大小，功能和重塑的影响。 2）确定慢性抗 H2S通过抑制NLRP3-炎症体和炎症作用 缺血性心肌病。 3）研究H2s在线粒体损伤衰减中的作用 MI后通过保留MAV和抑制Cofilin-2的炎症损伤的传播。这些 研究将是第一个证明H2S预防不良重塑的受保护作用的研究 跟随MI以及其在失败的心脏中潜在的治疗效用，可能通过衰减 炎症体介导的不良适应性信号传导。这是特别新颖的，结果将具有巨大的 对进一步认可H2S作为缺血性心力衰竭的潜在治疗剂的影响。而且，这些 研究将提供新的机械信息 精确控制的H2S释放导致整体心血管健康的改善。