Regulation of CSE-Derived Hydrogen Sulfide in the Heart

CSE 衍生的硫化氢在心脏中的调节

• 批准号: 10659832
• 负责人: John Winter Calvert
• 金额: $ 52.15万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10659832
• 关键词: 3-Mercaptopyruvate sulfurtransferase; 5' -AMP-activated protein kinase; Acute; Affect; Anabolism; Attention; Biology; Cardiac; Cardiovascular Diseases; Cardiovascular system; Cystathionine beta-Synthase; Cysteine; Cysteine Desulfhydrase; Cytoprotection; Data; Development; Diabetes Mellitus; Energy Metabolism; Enzymes; Experimental Models; Heart; Heart failure; High Fat Diet; Hydrogen Sulfide; In Vitro; Ischemia; Lipid Mobilization; Lipids; Mitochondria; Myocardial Reperfusion Injury; Nutrient; Pathologic; Pathology; Pathway interactions; Phosphorylation; Phosphorylation Site; Physiological; Play; Post-Translational Protein Processing; Process; Production; Proteins; Regulation; Reporting; Role; Serine; Signal Pathway; Signaling Molecule; Stimulus; Stress; Testing; beta-mercaptopyruvate; cardioprotection; combat; diet-induced obesity; experimental study; genetic approach; in vivo; insight; novel therapeutics; nutrient deprivation; oxidation; perilipin; persulfides; pressure; protein expression; protein function; recruit; response; sulfhydration

Project Summary Hydrogen sulfide (H2S) is an endogenously produced signaling molecule that impacts protein function by modifying cysteine residues through the formation of a persulfide bond by a process termed sulfhydration (persulfidation). It is produced enzymatically by three enzymes in the cysteine biosynthesis pathway: cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS), and 3-mercaptopyruvate sulfutransferase (3- MST). Numerous studies have reported a protective role for H2S in experimental models of acute myocardial ischemia-reperfusion injury and heart failure. While these studies and others have established a cytoprotective role for H2S, there are still unresolved questions regarding the biology of H2S. For instance, there is a lack of understanding in how the endogenous production of H2S is regulated. Additionally, there is a need to identify protein targets of H2S in response to different stimuli to unravel the mechanism by with H2S impacts adaptation to stress. This proposal aims to offer new insights into the regulation of the H2S-producing activity of CSE. We present new data that AMP-activated protein kinase (AMPK) increases CSE-derived H2S production via phosphorylation of serine 126. Further studies identified perilipin 5 (Plin5) – a protein that promotes the association of lipid droplets with mitochondria - as a protein modified by sulfhydration following nutrient deprivation and AMPK activation. Our data also shows that the interaction of lipid droplets with mitochondria following nutrient deprivation is dependent on CSE. Based on this evidence, we hypothesize that in response to nutrient stress, AMPK induces the H2S-producing activity of CSE to impart adaptive cellular mechanisms. Specifically, we hypothesize that CSE-derived H2S maintains energy metabolism during nutrient stress by regulating the mobilization of lipid droplets to the mitochondria, in part, by altering the sulfhydration of Plin5. In Aim 1, we will investigate the impact of serine 126 phosphorylation on the H2S-producing activity of CSE. In Aim 2, we will investigate the Impact of CSE-derived H2S on maintaining Lipid Droplet-fueled β-oxidation during nutrient deprivation. In Aim 3, we will determine the impact of sulfhydration on Plin5 during nutrient deprivation. This project breaks new ground in defining a mechanism by which the H2S-producing activity of CSE is regulated. As such, it has the potential to lead to the development of novel therapies aimed at harnessing the physiological effects of H2S to combat cardiovascular disease.

项目摘要 硫化氢（H2S）是一种内源性产生的信号分子，通过以下方式影响蛋白质功能： 通过形成过硫键修饰半胱氨酸残基 （过硫化）。它由半胱氨酸生物合成途径中的三种酶酶促产生： 胱硫醚-γ-裂解酶（CSE）、胱硫醚-β-合成酶（CBS）和3-巯基丙酮酸硫酸转移酶（3- MST）。许多研究报道了H2S在急性心肌损伤实验模型中的保护作用。 缺血-再灌注损伤和心力衰竭。虽然这些研究和其他研究已经建立了细胞保护机制， 尽管H2S的生物学作用尚未得到解决，但关于H2S的生物学仍然存在未解决的问题。例如，缺乏 了解H2S的内源性产生是如何调节的。此外，还需要确定 H2S蛋白靶点对不同刺激的响应，通过对H2S影响的适应机制的揭示 来强调。该提案旨在为CSE产生H2S活性的调节提供新的见解。我们 提出了新的数据，AMP激活的蛋白激酶（AMPK）增加CSE衍生的H2S的生产，通过 丝氨酸的磷酸化126.进一步的研究确定了perilipin 5（Plin 5）-一种促进细胞凋亡的蛋白质。 脂滴与线粒体的关联-作为营养后通过硫水合修饰的蛋白质 剥夺和AMPK激活。我们的数据还表明，脂滴与线粒体的相互作用 在营养缺乏后，依赖于CSE。基于这些证据，我们假设， 对于营养胁迫，AMPK诱导CSE产生H2S的活性以赋予适应性细胞机制。 具体来说，我们假设CSE衍生的H2S通过以下方式维持营养胁迫期间的能量代谢： 调节脂滴向线粒体的移动，部分是通过改变Plin 5的巯基化。在 目的1，我们将研究丝氨酸126磷酸化对CSE产生H2S活性的影响。在 目的2，我们将研究CSE衍生的H2S对维持脂滴燃料β-氧化的影响 在营养缺乏的情况下。在目标3中，我们将确定在营养过程中硫化对Plin 5的影响。 剥夺该项目在定义一种机制方面取得了新的进展， CSE是规范的。因此，它有可能导致新疗法的发展， 利用H2S的生理效应来对抗心血管疾病。