CSE regulation of vascular remodeling

项目摘要 硫化氢的合成和代谢是心血管健康和功能的重要参与者。 具体地说，我们的实验室已经证明了胱硫氨酸裂解酶(CSE)的表达和功能起着至关重要的作用 动脉生成和血管生成在缺血性血管重塑反应中的作用。此外，我们集团还拥有 揭示了硫化物和一氧化氮之间重要的化学生物学和病理生理关系 临床血管疾病条件下的代谢物，这可能是重要的协同调节 缺血性血管重塑。然而，许多分子和细胞机制仍然完全存在。 这些反应中未知的包括：特定细胞群体在产生离散硫化物物种中的作用 在缺血性血管重塑过程中，不同硫化物代谢产物如何调节一氧化氮(NO) 通过各种生化途径和调节CSE快速增加的机制实现生物利用度 低氧时活性依赖的硫化物代谢产物的生物利用度。此应用程序将解决以下问题 利用新的组织特异性CSE突变小鼠模型，前沿分析重要未知区域 硫化物和NO的化学测量方法，细胞和分子方法 低氧条件下CSE蛋白活性的翻译后调节，临床组织标本 更好地了解过硫化物和多硫化物在血管重塑和疾病中的作用。使用模型和 工具，这项提议将检验内皮细胞和单核细胞CSE依赖的假设 多硫化物的形成不同地调节缺血血管重塑和无生物利用度。三 具体目标将包括：1)确定内皮细胞CSE的机制 缺血性血管重构的调节及其如何控制血管细胞NO的生物利用度，2)确定 单核细胞CSE调节动脉生成的机制；3)决定CSE活性的机制 并在实验模型和临床标本中表达。该项目的完成将提供至关重要的 关于CSE调节机制和多硫化物的新的基本见解目前尚不清楚 缺血性血管重塑对细胞生物学的影响。

Project Summary Hydrogen sulfide synthesis and metabolism is an important participant in cardiovascular health and function. Specifically, our laboratory has shown that cystathionine g-lyase (CSE) expression and function play a critical role in ischemic vascular remodeling responses of arteriogenesis and angiogenesis. Moreover, our group has revealed important chemical biology and pathophysiological relationships between sulfide and nitric oxide metabolites in clinical vascular disease conditions, which may be important for cooperative regulation of ischemic vascular remodeling. However, numerous molecular and cellular mechanisms remain completely unknown in these responses including: the role of specific cell populations in producing discrete sulfide species during ischemic vascular remodeling, how different sulfide metabolites modulate nitric oxide (NO) bioavailability through various biochemical pathways, and mechanisms regulating rapid increases in CSE activity dependent sulfide metabolite bioavailability during hypoxia. This application will address these important unknown areas using novel tissue specific CSE mutant mouse models, cutting edge analytical chemistry measurement methods of sulfide and NO species, cellular and molecular methods to discover posttranslational regulation of CSE protein activity in response to hypoxia, and clinical tissue specimens to better understand persulfide and polysulfide during vascular remodeling and disease. Using the models and tools above, this proposal will examine the hypothesis that endothelial cell and monocyte CSE dependent polysulfide formation differentially regulates ischemic vascular remodeling and NO bioavailability. Three specific aims will be pursued to test the hypothesis including: 1) determine the mechanisms of endothelial CSE regulation of ischemic vascular remodeling and how it controls vascular cell NO bioavailability, 2) determine the mechanisms of monocyte CSE regulation of arteriogenesis, and 3) determine mechanisms of CSE activity and expression in experimental models and clinical specimens. Completion of this project will provide crucial new basic insight that is not currently available regarding mechanisms of CSE regulation and polysulfide effects on cell biology during ischemic vascular remodeling.