Endogenous Hydrogen Sulfide Enzymes in Heart Failure

心力衰竭中的内源性硫化氢酶

基本信息

  • 批准号:
    10321646
  • 负责人:
  • 金额:
    $ 40.13万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

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.
心力衰竭(HF)是美国心血管死亡率和发病率的主要原因。 尽管目前的治疗,患有HF的患者遭受生活质量差和寿命缩短。 需要对HF的关键病理机制有更好的理解, 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传导, 关键调节心血管稳态的分子。H2S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。先前 我们小组的工作表明,外源性H2S产生了强有力的 在心力衰竭动物模型中的心脏保护作用。我们已经证明基因靶向小鼠 过表达内源性H2S产生酶的细胞在HF环境中受到保护。H2S是 由胱硫醚γ-裂解酶(CSE)、胱硫醚β-合酶 (CBS)和3-巯基丙酮酸硫转移酶(3-MST)。CSE、CBS和3-MST均表达 在心脏和循环,但表现出显着差异,其调节和细胞 本地化我们提出的研究的中心假设是,H2S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)发挥 在HF发病机制中具有明显的心脏保护作用。尽管我们已经证明 H2S水平在实验室动物和患者的心脏和循环中降低, 心力衰竭,H2S可用性降低的原因和后果的特征很差。我们 已经开发出了新的功能获得和丧失小鼠模型, 关于CSE、CBS和3-MST对HF发生和进展的贡献。我们将 采用多方面的方法,包括生理,分子,生物化学,遗传, 药理学方法来阐明内源性硫化氢在心力衰竭中的作用。拟议 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传导,以评估 内源性H2S对HF病理生物学的影响。 具体而言,我们将:(1)确定所有三种内源性H2S表达的时间过程 产生酶以及压力超负荷和心肌中H2S生物利用度水平 (2)直接研究H2S产生酶在心肌梗死诱导的HF中的作用。 通过使用细胞类型特异性基因靶向治疗, CSE、CBS和3-MST功能获得和丧失的小鼠模型;(3)鉴定新的 通过内源性H2S产生酶介导的内源性细胞保护信号级联, 早期和晚期压力超负荷和心肌梗死诱发HF。 这些研究的成功完成将进一步加深我们对HF发病机制的理解, 将提供制定改进的药理学策略所需的关键信息 利用H2S疗法造福HF患者。

项目成果

期刊论文数量(17)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Obstructive Sleep Apnea: The Not-So-Silent Killer.
  • DOI:
    10.1161/circresaha.119.316359
  • 发表时间:
    2020-01
  • 期刊:
  • 影响因子:
    20.1
  • 作者:
    T. Goodchild;D. Lefer
  • 通讯作者:
    T. Goodchild;D. Lefer
Endothelial Cell Cystathionine γ-Lyase Expression Level Modulates Exercise Capacity, Vascular Function, and Myocardial Ischemia Reperfusion Injury.
  • DOI:
    10.1161/jaha.120.017544
  • 发表时间:
    2020-10-20
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Xia H;Li Z;Sharp TE 3rd;Polhemus DJ;Carnal J;Moles KH;Tao YX;Elrod J;Pfeilschifter J;Beck KF;Lefer DJ
  • 通讯作者:
    Lefer DJ
Hydrogen Sulfide as a Potential Therapy for Heart Failure-Past, Present, and Future.
  • DOI:
    10.3390/antiox10030485
  • 发表时间:
    2021-03-19
  • 期刊:
  • 影响因子:
    0
  • 作者:
    LaPenna KB;Polhemus DJ;Doiron JE;Hidalgo HA;Li Z;Lefer DJ
  • 通讯作者:
    Lefer DJ
Nonlethal Inhibition of Gut Microbial Trimethylamine N-oxide Production Improves Cardiac Function and Remodeling in a Murine Model of Heart Failure.
  • DOI:
    10.1161/jaha.119.016223
  • 发表时间:
    2020-05-18
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Organ CL;Li Z;Sharp TE 3rd;Polhemus DJ;Gupta N;Goodchild TT;Tang WHW;Hazen SL;Lefer DJ
  • 通讯作者:
    Lefer DJ
Common Heart Failure With Preserved Ejection Fraction Animal Models Yield Disparate Myofibril Mechanics.
具有保留射血分数的常见心力衰竭动物模型会产生不同的肌原纤维力学。
  • DOI:
    10.1161/jaha.123.032037
  • 发表时间:
    2024
  • 期刊:
  • 影响因子:
    5.4
  • 作者:
    Fenwick,AxelJ;Jani,VivekP;Foster,DBrian;Sharp,ThomasE;Goodchild,TraciT;LaPenna,Kyle;Doiron,JakeE;Lefer,DavidJ;Hill,JosephA;Kass,DavidA;Cammarato,Anthony
  • 通讯作者:
    Cammarato,Anthony
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