Endogenous Hydrogen Sulfide Enzymes in Heart Failure

心力衰竭(HF)是美国心血管疾病死亡和发病率的主要原因。 尽管目前有治疗方法，但心力衰竭患者的生活质量较差，寿命缩短。 需要对心力衰竭的关键病理机制有更深入的了解 开发新的治疗方法。硫化氢(H2S)是一种强有力的内源性气体信号 关键调节心血管动态平衡的分子。硫化氢调节血压，抑制 细胞凋亡和炎症，保护线粒体，并发挥强大的抗氧化作用。上一首 我们小组的研究表明，外源注射的硫化氢会产生强大的 心力衰竭动物模型的心脏保护作用。我们已经证明了以基因为靶标的小鼠 过量表达内源H_2S产生的酶在HF环境中受到保护。硫化氢是 由胱硫醚γ裂解酶、胱硫醚β合成酶三种酶内源产生 (CBS)和3-巯基丙酮酸硫化转移酶(3-MST)。CSE、CBS和3-MST均有表达 在心脏和循环中，但在它们的调节和细胞方面表现出显著的差异 本地化。我们对拟议研究的中心假设是，硫化氢来自不同的 酶，在不同的细胞群(内皮细胞、心肌细胞、成纤维细胞)中发挥作用 心衰发病机制中明显的心肌保护作用。不过，我们已经证明了 实验动物和患者的心脏和循环中的硫化氢水平都降低了 心力衰竭、硫化氢可获得性降低的原因和后果的描述很差。我们 开发了新的功能获得和功能丧失模型，将提供机械洞察力 关于CSE、CBS和3-MST对心力衰竭的发展和进展的贡献。我们会 采用多方面的方法，包括生理、分子、生化、遗传和 阐明内源性硫化氢在心力衰竭中的作用的药理学方法。建议数 研究将评估左心室结构和功能，心脏纤维化，运动能力， 血管功能、线粒体生物能量学和分子信号转导来评估血管紧张素转换酶的作用 内源性硫化氢对心力衰竭病理生物学的影响。 具体地说，我们将：(1)确定所有三种内源性H_2S表达的时间进程 压力超负荷和心肌组织中H_2S生物有效性及产生酶的研究 (2)直接研究H_2S产生酶在心力衰竭中的作用。 应用细胞类型特异性基因靶向研究心力衰竭的病理学进展 CSE、CBS和3-MST功能得失的小鼠模型；(3)识别新的 内源H_2S产生酶介导的内源细胞保护信号级联反应 早期和晚期压力超负荷和心肌梗死诱发心力衰竭。 这些研究的成功完成将进一步加深我们对心力衰竭发病机制的了解。 将提供开发改进的药理学策略所需的关键信息 利用硫化氢治疗，造福心力衰竭患者。

Heart failure (HF) is a leading cause of cardiovascular mortality and morbidity in the United States. Despite current treatments, patients with HF suffer from a poor quality of life and reduced lifespan. An improved understanding of the critical pathological mechanisms of HF is required for the development of novel therapies. Hydrogen sulfide (H2S) is a potent endogenous, gaseous signaling molecule that critically regulates cardiovascular homeostasis. H2S regulates blood pressure, inhibits apoptosis and inflammation, protects mitochondria, and exerts powerful antioxidant actions. Previous work from our group has shown that exogenously administered H2S produces robust cardioprotective effects in animal models of heart failure. We have shown that gene-targeted mice that overexpress endogenous H2S producing enzymes are protected in the setting of HF. H2S is generated endogenously by three enzymes cystathionine γ-lyase (CSE), cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtranseferase (3-MST). CSE, CBS and 3-MST are all expressed in the heart and circulation, but exhibit significant differences in their regulation and cellular localization. Our Central Hypothesis for the proposed studies is that H2S derived from different enzymes, in different cell populations (endothelial cells, cardiac myocytes, fibroblasts) exerts distinct cardioprotective effects in the pathogenesis of HF. Although, we have demonstrated that H2S levels are reduced in the heart and circulation of both laboratory animals and patients with heart failure, the causes and consequences of reduced H2S availability are poorly characterized. We have developed novel gain and loss of function mouse models that will provide mechanistic insights regarding the contribution of CSE, CBS and 3-MST to HF development and progression. We will employ a multifaceted approach that includes physiological, molecular, biochemical, genetic, and pharmacological approaches to elucidate the role of endogenous H2S in heart failure. The proposed studies will evaluate left ventricular structure and function, cardiac fibrosis, exercise capacity, vascular function, mitochondrial bioenergetics, and molecular signaling to evaluate the role of endogenous H2S on the pathobiology of HF. Specifically, we will: (1) determine the time course of expression of all three endogenous H2S generating enzymes as well as the levels of H2S bioavailability in pressure overload and myocardial infarction induced HF; (2) directly investigate the contribution of H2S-producing enzymes in the development and progression of HF pathology through the use of cell type-specific gene-targeted mouse models with gain and loss of function for CSE, CBS, and 3-MST; (3) identify novel endogenous cytoprotective signal cascades mediated via endogenous H2S producing enzymes in the early and late stages of pressure overload and MI induced HF. Successful completion of these studies will further our understanding of the pathogenesis of HF and will provide critical information required for the development of improved pharmacological strategies to harness H2S therapy for the benefit of patients with HF.