Hydrogen Sulfide for Prevention and Treatment of Ischemic Heart Failure

项目摘要 硫化氢(H2s)是一种强大的气体传递器，已被证明具有强大的保护作用。 对心脏和其他器官的缺血相关损伤的影响。国际和平研究所最近的创新研究和 同事们已经确定了调节内源性H_2S水平以介导 磷酸二酯酶-5抑制剂他达拉非以及一种强大的一氧化氮(NO)非依赖性鸟苷环化酶 激活剂Cinaciguat，在小鼠的心脏中。PI实验室的最新研究表明， 外源性硫化氢对脑缺血/再灌注损伤的保护和抗炎作用 以及胱硫醚-γ裂解酶驱动的硫化氢生成在介导基因的心脏保护效应中的作用 蛋白激酶G治疗的目的是进一步研究新的机制，通过 哪种硫化氢能减轻衰竭患者的缺血性心肌病和炎症体介导的不良重构 心。我们将检验以下假设：1)调查硫化氢对预防的保护作用 心肌梗死(MI)后不良重塑和缺血性心力衰竭的缓解。我们会 研究硫化氢对左心室瘢痕大小、功能及重塑的影响。2)测定慢性抗-HBs H_2S抑制NLRP3-炎症小体的炎症效应及其演变 缺血性心肌病。3)研究硫化氢在减轻线粒体损伤中的作用 心肌梗死后通过保留MAV和抑制Cofilin-2的炎性损伤的传播。这些 研究将首次证明硫化氢对防止不良重塑的保护作用。 心肌梗塞后，以及它对衰竭心脏的潜在治疗作用，可能是通过减弱 炎症体介导的适应不良信号。这是特别新颖的，结果将会有巨大的 进一步认可硫化氢作为治疗缺血性心力衰竭的有效药物的影响。此外，这些 研究将提供新的机制信息，通过这些信息，新的合成药理剂与 精确控制的硫化氢排放有助于改善整体心血管健康状况。

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.