Assessment of hydrogen sulfide in vascular biology

血管生物学中硫化氢的评估

• 批准号: 6986258
• 负责人: DAVID W KRAUS
• 金额: $ 21.81万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6986258
• 关键词: aorta; biological signal transduction; blood vessels; chemical structure function; homeostasis; homocysteine; homocystinuria; hydrogen sulfide; inflammation; laboratory rat; oxidation reduction reaction; oxidative stress; posttranslational modifications; vasomotion

DESCRIPTION (provided by applicant): Hydrogen sulfide (H2S) is produced in many mammalian tissues and has been detected in micromolar amounts in blood and brain tissue. Although its potential to participate in cell signaling is clear, this biological role is not well understood. H2S, analogous to nitric oxide (NO), is produced by amino acid metabolism, readily diffuses through tissue, and is rapidly oxidized. H2S is a competent nucleophile and reductant, capable of post-translational protein modification such as ligand displacement from heme iron and dithiol reduction. In addition, H2S under physiological conditions can readily react stoichiometrically with S-nitrosothiols (RSNO) to release NO. The dynamic processes of H2S production and consumption that control cellular H2S levels respond to cellular redox status. Activity of cystathionine beta synthase (CBS) increases under oxidative stress to catalyze both H2S production and homocysteine (Hcy) breakdown. Hey, is linked to the development of atherosclerosis and neurodegeneration, and impairs NO-mediated vasorelaxation. The vascular dysfunction in hyperhomocysteinemia may be a result of decreased H2S levels. H2S is a potent vascular signal that can mediate vasoconstriction or vasorelaxation depending on O2 level and tissue. In the rat aorta, H2S concentrations that mediate rapid constriction at one O2 level will cause rapid relaxation at lower O2 levels. These results and others indicate that H2S vasoactive mechanisms include both NO-independent and NO-dependent pathways such as RSNO metabolism. The sepsis model may prove ideal for the experimental manipulation of these phenomena. Elevated vascular NO and RSNO levels during the development of sepsis contribute to hypotensive shock. H2S metabolism of RSNO under these conditions would lead to increased bioavailability of NO and may exacerbate loss of vessel tone. Because H2S, like NO, is rapidly oxidized, a novel polarographic sulfide sensor (PSS) invented in my laboratory has been a major methodological tool used to define H2S effects on vascular function. We propose to test the central hypothesis that, in the vascular, H2S is a key O2-dependent regulator of vascular function under physiological and pathological conditions. The components of this hypothesis will be explored in the following specific aims. AIM 1. Determine the homeostatic mechanisms that directly regulate H2S production and consumption with emphasis on conditions that can perturb cellular redox status AIM 2. Determine the mechanisms of O2-dependent H2S control of vessel tension under normal and inflammatory disease conditions.

描述（由申请人提供）：硫化氢（H2S）在许多哺乳动物组织中产生，并已在血液和脑组织中检测到微摩尔量。虽然它参与细胞信号传导的潜力是明确的，但这种生物学作用还没有得到很好的理解。H2S类似于一氧化氮（NO），由氨基酸代谢产生，易于通过组织扩散，并迅速氧化。H2S是一种有能力的亲核试剂和还原剂，能够进行翻译后蛋白质修饰，如血红素铁的配体置换和二硫醇还原。此外，H2S在生理条件下可以容易地与S-亚硝基硫醇（RSNO）化学计量反应释放NO。控制细胞H2S水平的H2S产生和消耗的动态过程响应于细胞氧化还原状态。胱硫醚β合酶（CBS）的活性在氧化应激下增加，以催化H2S产生和同型半胱氨酸（Hcy）分解。与动脉粥样硬化和神经变性的发展有关，并损害NO介导的血管舒张。高同型半胱氨酸血症的血管功能障碍可能是H2S水平降低的结果。H2S是一种有效的血管信号，可根据O2水平和组织介导血管收缩或血管舒张。在大鼠主动脉中，在一个O2水平下介导快速收缩的H2S浓度将在较低O2水平下引起快速舒张。这些结果和其他结果表明，H2S血管活性机制包括NO非依赖性和NO依赖性途径，如RSNO代谢。脓毒症模型可能被证明是理想的实验操作这些现象。在脓毒症的发展过程中，血管NO和RSNO水平升高有助于水肿性休克。在这些条件下RSNO的H2S代谢将导致NO的生物利用度增加，并可能加剧血管张力的丧失。因为H2S，像NO，是迅速氧化，一种新型的极谱硫化物传感器（PSS）在我的实验室发明了一个主要的方法工具，用于定义H2S对血管功能的影响。我们建议测试中心的假设，在血管，硫化氢是一个关键的O2依赖性调节血管功能的生理和病理条件下。这一假设的组成部分将在以下具体目标中加以探讨。AIM 1.确定直接调节H2S生产和消费的稳态机制，重点是可以扰乱细胞氧化还原状态AIM 2的条件。确定在正常和炎症性疾病条件下O2依赖性H2S控制血管张力的机制。