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.

项目概要 硫化氢 (H2S) 是一种强大的气体递质，已被证明具有强大的保护作用 PI 和其他器官最近的创新研究对心脏和其他器官的缺血相关损伤的影响。 同事们已经确定了内源性 H2S 水平的调节来介导心脏保护作用 磷酸二酯酶 5 抑制剂、他达拉非以及有效的一氧化氮 (NO) 独立鸟苷酸环化酶 PI实验室最近的研究证明了这种激活剂Cinaciguat在小鼠心脏中的作用。 外源性 H2S 对缺血/再灌注 (I/R) 损伤的梗塞保留和抗炎作用 以及胱硫醚-γ-裂解酶驱动的 H2S 生成在介导基因心脏保护作用中的作用 蛋白激酶 G 疗法。本申请的目的是通过以下方式进一步研究新机制： H2S 可减轻缺血性心肌病和衰竭中炎症体介导的不良重塑 我们将检验以下假设： 1) 研究 H2S 对预防的保护作用。 心肌梗死（MI）后的不良重塑和缺血性心力衰竭的缓解我们将进行研究。 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 炎症小体的炎症作用及其​​进化 3) 研究H2S在减轻线粒体损伤和治疗中的作用。 通过保留 MAVS 和抑制 cofilin-2 来抑制 MI 后炎症损伤的传播。 研究将首次证明 H2S 对预防不良重塑的保护作用 心肌梗死后的治疗效果及其对心脏衰竭的潜在治疗作用，可能是通过减弱 炎症体介导的适应不良信号传导尤其新颖，其结果将产生巨大的影响。 对进一步认可 H2S 作为缺血性心力衰竭的有效治疗剂的影响。 研究将提供新的机制信息，通过这些信息，新的合成药物制剂 精确控制的 H2S 释放可改善整体心血管健康。