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: 9277553
• 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/9277553
• 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; Inflammasome; Inflammation; Inflammatory; Injury; Ischemia; Knockout Mice; Knowledge; Laboratories; Lead; Ligation; Lyase; Mediating; Metabolism; Mitochondria; Modeling; Modification; Molecular Profiling; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Nitric Oxide; Obstruction; Organ; Oxidative Stress; Patients; Pharmacology; Phosphorylation; Physiological; Prevention; Process; Production; Property; Proteins; Regulation; Reperfusion Injury; Reperfusion Therapy; Reporting; Role; Saline; Signal Transduction; Signaling Protein; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Translating; attenuation; base; biological systems; cardiovascular health; cell injury; cofilin 2; design; gene therapy; improved; 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.

项目总结