Dysfunction of protection enzymes of vascular endothelial cell surface results in the pathogenesis of cardiovascular disease
血管内皮细胞表面保护酶功能障碍导致心血管疾病发病
基本信息
- 批准号:12672113
- 负责人:
- 金额:$ 2.11万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (C)
- 财政年份:2000
- 资助国家:日本
- 起止时间:2000 至 2001
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Extracellular-superoxide dismutase (EC-SOD) is a secretory glycoprotein with an affinity for heparin-like substances. The plasma EC-SOD level might affect physiological and pathological conditions of the vascular system since this enzyme is the principal enzymatic scavenger of superoxide in the extracellular space and is present in the circulation in equilibrium between the plasma phase and the glycosaminoglycans on the endothelium.Modest elevation of plasma homocysteine, commonly referred to as hyperhomocysteinemia, is generally considered to be a risk factor for coronary, cerebral and peripheral vascular disease and thrombosis. While the mechanisms mediating vascular changes are still unclear, there is evidence that elevated plasma homocysteine may cause endothelial cell injury or dysfunction. We hypothesized that homocysteine causes degradation of endothelial cell function, followed by detachment of EC-SOD from the endothelium and elevation of plasma EC-SOD. The present study was de … More signed to elucidate the mechanism by which homocysteine increased the plasma EC-SOD level and modulated endothelial cell function. Firstly, we observed that there was a significant correlation between plasma homocysteine and EC-SOD levels. Next, this study demonstrated that binding of EC-SOD to endothelial cell surfaces was significantly decreased by pretreatment with a low concentration of homocysteine, which might have been due to the dysfunction of heparan sulfate proteoglycan on the cells. While further studies are needed to explore these mechanisms, these findings suggest that homocysteine may decrease the protection of vascular endothelial cell surfaces from superoxide anion and result in the pathogeneses of atherosclerosis and cardiovascular disease.Nitric oxide (NO) is produced by three distinct isoforms of nitric oxide synthase (NOS) and regulates physiological and pathological events in cellular systems. The induction of inducible NOS (iNOS) is involved in the inflammatory process evoked by endogenous signals such as infectious agents, lipopolysaccharide (LPS) and inflammatory cytokines, in phagocytes and other cells. Excessive amounts of NO are associated with plasma leakage and microvascular injury as well as cytotoxic effects against host cells in the inflammatory focus. In this study, we found that exogenous NO decreased r-EC-SOD binding to the endothelial cell surface. It is known that large amounts of NO were produced by several cells including macrophages, endothelial cells and smooth muscle cells, stimulated by inflammatory cytokines or LPS. We found that the co-culture with LPS-stimulated J774 A-l cells decreased the binding ability of HUVEC with r-EC-SOD. These results suggest that large amounts of NO released from activated macrophages would cause the decrease of EC-SOD-binding to the endothelial cell surface, followed by the decrease of capacity to scavenge superoxide in the microenvironment of the vascular system, causing vascular injury, our study demonstrated that the binding of EC-SOD to glycosaminoglycans was significantly decreased by macrophagederived NO, and NO donors and their decomposed derivatives, especially nitrite. These findings suggest that excess NO decreases the protection of the vascular endothelial cell surface from superoxide and results in the pathogenesis of inflammation and the other oxidative stressderived diseases. Less
细胞外超氧化物歧化酶(EC-SOD)是一种分泌型糖蛋白,对肝素样物质具有亲和力。血浆EC-SOD水平可能影响血管系统的生理和病理状态,因为这种酶是细胞外空间中超氧化物的主要酶清除剂,并且存在于循环中,在血浆相和内皮上的糖胺聚糖之间处于平衡状态。血浆同型半胱氨酸的适度升高,通常被称为高同型半胱氨酸血症,通常被认为是冠状动脉疾病的危险因素,脑和外周血管疾病和血栓形成。虽然介导血管变化的机制尚不清楚,但有证据表明血浆同型半胱氨酸升高可能导致内皮细胞损伤或功能障碍。我们推测同型半胱氨酸导致内皮细胞功能下降,随后EC-SOD从内皮细胞上脱落,血浆EC-SOD升高。本研究旨在 ...更多信息 旨在阐明同型半胱氨酸增加血浆EC-SOD水平和调节内皮细胞功能的机制。首先,我们观察到血浆同型半胱氨酸与EC-SOD水平之间存在显著相关性。接下来,这项研究表明,结合EC-SOD的内皮细胞表面显着降低预处理与低浓度的同型半胱氨酸,这可能是由于硫酸乙酰肝素蛋白多糖对细胞的功能障碍。这些研究结果表明,同型半胱氨酸可降低血管内皮细胞表面对超氧阴离子的保护作用,从而导致动脉粥样硬化和心血管疾病的发生。一氧化氮(NO)由三种不同的一氧化氮合酶(NOS)亚型产生,调节细胞系统的生理和病理事件。诱导型一氧化氮合酶(inducible NOS,iNOS)的诱导参与了吞噬细胞和其他细胞中由内源性信号如感染因子、脂多糖(lipopolysaccharide,LPS)和炎性细胞因子诱发的炎症过程。过量的NO与血浆渗漏和微血管损伤以及对炎症病灶中宿主细胞的细胞毒性作用相关。在本研究中,我们发现,外源性NO降低r-EC-SOD与内皮细胞表面的结合。已知在炎性细胞因子或LPS刺激下,包括巨噬细胞、内皮细胞和平滑肌细胞在内的多种细胞产生大量NO。结果发现,LPS刺激的J774 A-1细胞与HUVEC共培养后,HUVEC与r-EC-SOD的结合能力降低。这些结果表明,激活的巨噬细胞释放大量NO,会导致EC-SOD与内皮细胞表面结合能力下降,继而降低清除血管系统微环境中超氧阴离子的能力,引起血管损伤。我们的研究表明,巨噬细胞源性NO、NO供体及其分解衍生物可显著降低EC-SOD与糖胺聚糖的结合,尤其是亚硝酸盐。这些结果表明,过量的NO降低了血管内皮细胞表面对超氧化物的保护,并导致炎症和其他氧化应激源性疾病的发病机制。少
项目成果
期刊论文数量(84)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Tetsuo Adachi, et al.: "Age-related change of plasma extracellular-superoxide dismutase"Clin. Chim. Acta. 290. 169-178 (2000)
Tetsuo Adachi 等人:“血浆细胞外超氧化物歧化酶的年龄相关变化”临床。
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- 影响因子:0
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前畑英介: "糖尿病患者を対象とした酸化LDLレベルと顆粒球エラスターゼとの関連性"日本臨床検査自動化学会会誌. 25. 641-645 (2000)
Eisuke Maehata:“糖尿病患者氧化 LDL 水平与粒细胞弹性蛋白酶之间的关系”日本临床实验室自动化学会杂志 25. 641-645 (2000)。
- DOI:
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- 影响因子:0
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Masayuki Yamamoto, et al.: "Nitric oxide and its decomposed derivatives decrease the binding of extracellular-superoxide dismutase to the endothelial cell surface"FEBS Lett.. 505. 296-300 (2001)
Masayuki Yamamoto 等人:“一氧化氮及其分解衍生物减少细胞外超氧化物歧化酶与内皮细胞表面的结合”FEBS Lett.. 505. 296-300 (2001)
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- 影响因子:0
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Tetsuo Adachi: "Experimental protocols for reactive oxygen and nitrogen species"Naoyuki Taniguchi, John M. C. Gutteridge(Oxford University Press). 5 (2000)
Tetsuo Adachi:“活性氧和氮物种的实验方案”Naoyuki Taniguchi,John M. C. Gutteridge(牛津大学出版社)。
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- 影响因子:0
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- 通讯作者:
Satoshi Iyama, et al.: "Treatmen of murine collagen-induced arthritis by ex vivo extracellular superoxide dismutase gene transfer"Arithritis Rheum.. 44. 2160-2167 (2001)
Satoshi Iyama 等人:“通过离体细胞外超氧化物歧化酶基因转移治疗鼠胶原诱导的关节炎”Arithritis Rheum.. 44. 2160-2167 (2001)
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ADACHI Tetsuo其他文献
ADACHI Tetsuo的其他文献
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{{ truncateString('ADACHI Tetsuo', 18)}}的其他基金
Contribution of impairment of redox-regulation in development of Intraretinal microvascular abnormalities
氧化还原调节受损在视网膜内微血管异常发展中的作用
- 批准号:
21590169 - 财政年份:2009
- 资助金额:
$ 2.11万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Regulation of anti-arteriosclerotic activity between anti-oxidative enzyme and adipocytokines
抗氧化酶和脂肪细胞因子之间抗动脉硬化活性的调节
- 批准号:
18590146 - 财政年份:2006
- 资助金额:
$ 2.11万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The medicine that functions to maintain the redox state might to the pathological conditions of insulin resistance
维持氧化还原状态的药物可能对胰岛素抵抗的病理状况有作用
- 批准号:
15590062 - 财政年份:2003
- 资助金额:
$ 2.11万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Application of endothelial cell-binding superoxide dismutase (EC-SOD) on screening of the initiation-progress of renal diseases
内皮细胞结合超氧化物歧化酶(EC-SOD)在肾脏疾病发生发展筛查中的应用
- 批准号:
10672044 - 财政年份:1998
- 资助金额:
$ 2.11万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Contribution of glutathione to multidrug resistance and the its regulation with active oxygen modulators
谷胱甘肽对多药耐药性的贡献及其活性氧调节剂的调节
- 批准号:
08672521 - 财政年份:1996
- 资助金额:
$ 2.11万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
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Heparan sulfate proteoglycan in the brain vascular clearance of amyloid-β and Alzheimer's disease
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Glycopolymer Inhibitors of Heparan Sulfate Proteoglycan Binding Pathogens
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In vitro investigation of (pro)IAPP binding to heparan sulfate proteoglycan
(pro)IAPP 与硫酸乙酰肝素蛋白聚糖结合的体外研究
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358571-2008 - 财政年份:2011
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In vitro investigation of (pro)IAPP binding to heparan sulfate proteoglycan
(pro)IAPP 与硫酸乙酰肝素蛋白聚糖结合的体外研究
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358571-2008 - 财政年份:2010
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Postgraduate Scholarships - Doctoral
Collagen X and heparan sulfate proteoglycan in the hematopoietic stem cell niche.
造血干细胞生态位中的 X 胶原蛋白和硫酸乙酰肝素蛋白多糖。
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8326237 - 财政年份:2010
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Collagen X and heparan sulfate proteoglycan in the hematopoietic stem cell niche.
造血干细胞生态位中的 X 胶原蛋白和硫酸乙酰肝素蛋白多糖。
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8146158 - 财政年份:2010
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Collagen X and heparan sulfate proteoglycan in the hematopoietic stem cell niche.
造血干细胞生态位中的 X 胶原蛋白和硫酸乙酰肝素蛋白多糖。
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7989286 - 财政年份:2010
- 资助金额:
$ 2.11万 - 项目类别:
In vitro investigation of (pro)IAPP binding to heparan sulfate proteoglycan
(pro)IAPP 与硫酸乙酰肝素蛋白聚糖结合的体外研究
- 批准号:
358571-2008 - 财政年份:2009
- 资助金额:
$ 2.11万 - 项目类别:
Postgraduate Scholarships - Doctoral