The assessment of hydrogen sulfide in vascular biology

描述(申请人提供)：硫化氢(硫化氢)在许多哺乳动物组织中产生，并在血液和脑组织中检测到微摩尔含量。尽管它参与细胞信号传递的潜力是显而易见的，但这种生物学作用还没有被很好地理解。硫化氢类似于一氧化氮(NO)，由氨基酸代谢产生，很容易在组织中扩散，并被迅速氧化。硫化氢是一种良好的亲核剂和还原剂，能够对蛋白质进行翻译后修饰，如从血红素铁置换配体和还原二硫醇。此外，在生理条件下，硫化氢很容易与S-亚硝硫醇(RSNO)发生化学计量比反应，释放出NO。控制细胞硫化氢水平的硫化氢产生和消耗的动态过程响应于细胞的氧化还原状态。在氧化应激下，胱硫醚β合成酶(CBS)的活性增加，以催化H_2S的生成和同型半胱氨酸(Hcy)的分解。嘿，与动脉粥样硬化和神经退行性变的发展有关，并损害NO介导的血管松弛。高同型半胱氨酸血症的血管功能障碍可能是由于H_2S水平降低所致。硫化氢是一种强有力的血管信号，根据氧气水平和组织的不同，它可以介导血管收缩或血管松弛。在大鼠的主动脉中，在一个氧气水平下调节快速收缩的硫化氢浓度将在较低的氧气水平下引起快速舒缩。这些结果和其他结果表明，硫化氢的血管活性机制包括NO依赖和NO依赖的途径，如RSNO代谢。脓毒症模型可能被证明是对这些现象进行实验操作的理想模型。脓毒症发展过程中血管NO和RSNO水平升高导致低血压休克。在这种情况下，RSNO的H_2S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。由于H_2S和NO一样被快速氧化，本实验室发明的新型极谱硫化物传感器(PSS)已成为确定H_2S对血管功能影响的主要方法工具。我们建议检验中心假设，在血管中，在生理和病理条件下，硫化氢是关键的O2依赖的血管功能调节因子。这一假设的组成部分将在以下具体目标中进行探讨。目的1.确定直接调节H_2S产生和消耗的动态平衡机制，重点是扰乱细胞氧化还原状态的条件。目的2.确定正常和炎症性疾病条件下氧依赖的H_2S控制血管张力的机制。

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.