Hydrogen Sulfide for Prevention and Treatment of Ischemic Heart Failure

项目摘要 硫化氢（H2S）是一种强有力的气体传递物，已被证明具有强大的保护作用， 对心脏和其他器官中缺血相关损伤的作用。PI最近的创新研究， 他的同事们已经确定了内源性H2S水平的调节介导了H2S的心脏保护作用。 磷酸二酯酶-5抑制剂他达拉非，以及一种强效的一氧化氮（NO）非依赖性鸟苷酸环化酶 激活剂Cinaciguat在小鼠心脏中。PI实验室最近的研究表明， 外源性H2S对缺血/再灌注（I/R）损伤的保护梗死和抗炎益处， 以及胱硫醚-γ-裂解酶驱动的H2S产生在介导基因的心脏保护作用中的作用。 蛋白激酶G治疗。本申请的目的是进一步研究新的机制， 其中H2S减弱了缺血性心肌病和炎性小体介导的不良重塑， 心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 研究硫化氢对左室瘢痕大小、功能和重塑的影响。2)为了确定慢性抗- H2S通过抑制NLRP 3-炎性体的炎性作用和 缺血性心肌病3)研究H2S在减轻线粒体损伤中的作用， 通过保留MAVS和抑制cofilin-2抑制MI后炎性损伤的传播。这些 研究将首次证明H2S对预防不良重塑的保护作用 以及其在衰竭心脏中的潜在治疗效用，可能通过减弱 炎性小体介导的适应不良信号传导。这是特别新颖的，其结果将有巨大的 进一步支持H2S作为缺血性心力衰竭的有效治疗剂的影响。而且这些 研究将提供新的机制信息， 精确控制的H2S释放导致整体心血管健康的改善。

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.