CSE regulation of vascular remodeling

CSE对血管重塑的调节

• 批准号: 10630127
• 负责人: Christopher G Kevil
• 金额: $ 42.8万
• 依托单位: LOUISIANA STATE UNIV HSC SHREVEPORT
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630127
• 关键词: Affect; American; Analytical Chemistry; Area; Binding; Biochemical Pathway; Biological Availability; Biology; Blood Vessels; Blood flow; Brain Hypoxia-Ischemia; Cardiovascular Diseases; Cardiovascular Physiology; Cells; Cellular biology; Chemicals; Chronic; Clinical; Cystathionine; Cysteine Desulfhydrase; Data; Disease; Endothelial Cells; Endothelium; Enzymes; Experimental Models; FDA approved; Generations; Glutathione Disulfide; Growth; Health; Hydrogen Sulfide; Hypoxia; Immune; In Vitro; Ischemia; Laboratories; Limb structure; Lyase; Macrophage; Macrophage Activation; Measurement; Mediator; Metabolism; Methods; Modality; Modeling; Molecular; Molecular Target; Mus; Nitric Oxide; Organ; Participant; Pathway interactions; Peripheral; Peripheral Vascular Diseases; Peripheral arterial disease; Permeability; Play; Population; Post-Translational Protein Processing; Post-Translational Regulation; Prevalence; Prevention; Production; Proliferating; Proteins; Regulation; Research; Risk Factors; Role; Signal Transduction; Specimen; Sulfides; Sulfur; Testing; Therapeutic; Tissues; Vascular Diseases; Vascular remodeling; Vascularization; angiogenesis; cardiovascular health; cell growth regulation; cofactor; critical limb Ischemia; cytokine; improved; insight; monocyte; mutant mouse model; novel; persulfides; polysulfide; recruit; response; therapeutically effective; tool

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.

项目概要 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，我们的实验室已表明胱硫醚 G-裂解酶 (CSE) 的表达和功能在 在动脉生成和血管生成的缺血性血管重塑反应中的作用。另外，我们组还有 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学关系 临床血管疾病条件下的代谢物，这对于协同调节可能很重要 缺血性血管重塑。然而，许多分子和细胞机制仍然完全保留 这些反应中未知的包括： 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) 通过各种生化途径的生物利用度以及调节 CSE 快速增加的机制 缺氧期间活性依赖的硫化物代谢物生物利用度。该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、尖端分析的重要未知领域 硫化物和NO物种的化学测量方法，发现的细胞和分子方法 CSE 蛋白活性响应缺氧的翻译后调节，以及临床组织标本 更好地了解血管重塑和疾病过程中的过硫化物和多硫化物。使用模型和 工具上述，该提案将检验内皮细胞和单核细胞 CSE 依赖的假设 多硫化物的形成对缺血性血管重塑和一氧化氮生物利用度有不同的调节作用。三 检验假设的具体目标包括：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 调节动脉生成的机制，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至关重要的 目前尚无关于 CSE 监管和多硫化物机制的新基本见解 缺血性血管重塑过程中对细胞生物学的影响。

项目成果

Bad Smells and Broken DNA: A Tale of Sulfur-Nucleic Acid Cooperation.

• DOI: 10.3390/antiox10111820
• 发表时间: 2021-11-17
• 期刊: Antioxidants (Basel, Switzerland)
• 作者: Shackelford RE;Li Y;Ghali GE;Kevil CG
• 通讯作者: Kevil CG

Plasma hydrogen sulfide: A biomarker of Alzheimer's disease and related dementias.

• DOI: 10.1002/alz.12305
• 发表时间: 2021-08
• 期刊: Alzheimer's & dementia : the journal of the Alzheimer's Association
• 作者: Disbrow E;Stokes KY;Ledbetter C;Patterson J;Kelley R;Pardue S;Reekes T;Larmeu L;Batra V;Yuan S;Cvek U;Trutschl M;Kilgore P;Alexander JS;Kevil CG
• 通讯作者: Kevil CG

Ethylmalonic Encephalopathy 1 Protein Is Increased in Colorectal Adenocarcinoma.

• DOI: 10.21873/anticanres.15286
• 发表时间: 2021-10
• 期刊: Anticancer research
• 影响因子: 2
• 作者: Ozluk E;Coppola D;Mohammad IZ;Islam T;Ghali G;Kevil CG;Shackelford RE
• 通讯作者: Shackelford RE

Molecular Functions of Hydrogen Sulfide in Cancer.

• DOI: 10.3390/pathophysiology28030028
• 发表时间: 2021-09-20
• 期刊: Pathophysiology : the official journal of the International Society for Pathophysiology
• 作者: Shackelford RE;Mohammad IZ;Meram AT;Kim D;Alotaibi F;Patel S;Ghali GE;Kevil CG
• 通讯作者: Kevil CG

Hypoxia increases persulfide and polysulfide formation by AMP kinase dependent cystathionine gamma lyase phosphorylation.

• DOI: 10.1016/j.redox.2023.102949
• 发表时间: 2023-12
• 期刊: REDOX BIOLOGY
• 影响因子: 11.4
• 作者: Alam, Shafiul;Pardue, Sibile;Shen, Xinggui;Glawe, John D.;Yagi, Takashi;Bhuiyan, Mohammad Alfrad Nobel;Patel, Rakesh P.;Dominic, Paari S.;Virk, Chiranjiv S.;Bhuiyan, Md Shenuarin;Orr, A. Wayne;Petit, Chad;Kolluru, Gopi K.;Kevil, Christopher G.
• 通讯作者: Kevil, Christopher G.