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。 具体来说，我们的实验室已经表明，胱硫醚裂解酶（CSE）的表达和功能在细胞凋亡中起着关键作用。 在动脉生成和血管生成的缺血性血管重塑反应中的作用。此外，我们的团队 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学关系 代谢物在临床血管疾病条件下，这可能是重要的合作调节， 缺血性血管重塑然而，许多分子和细胞机制仍然完全 这些反应中未知的因素包括：特定细胞群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，不同的硫化物代谢物如何调节一氧化氮（NO） 生物利用度通过各种生化途径，和机制调节CSE的快速增加， 活性依赖的硫化物代谢物在缺氧期间的生物利用度。本应用程序将解决这些问题 使用新型组织特异性CSE突变小鼠模型的重要未知领域， 硫化物和NO物种的化学测量方法，细胞和分子方法，以发现 CSE蛋白活性对缺氧反应的翻译后调节， 更好地了解血管重塑和疾病中的过硫化物和多硫化物。使用模型和 上述工具，本建议将检查内皮细胞和单核细胞CSE依赖性的假设， 多硫化物形成差异调节缺血性血管重塑和NO生物利用度。三 具体的目标将被追求，以检验这一假设，包括：1）确定内皮CSE的机制 缺血性血管重塑的调节及其如何控制血管细胞NO生物利用度，2）确定 单核细胞CSE调节动脉形成的机制; 3）确定CSE活性的机制 以及在实验模型和临床标本中的表达。该项目的完成将提供关键的 关于CSE调节机制和多硫化物的新的基本见解， 对缺血性血管重塑过程中细胞生物学的影响。

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.