The elucidation of the roles of cell-adhesion molecules in heart diseases

阐明细胞粘附分子在心脏病中的作用

• 批准号: 05557039
• 负责人: YAZAKI Yoshio
• 金额: $ 7.81万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Developmental Scientific Research (B)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-05557039/
• 关键词: cell-adhesion molecules; hypoxia; reoxygenation; MAP kinase; Rar-1 kinase; S6 kinase; myocardial infarction; myocarditis; transplantation; MAP キナーゼ; Raf-1 キナーゼ; Romano-Ward 症候群; S6 キナーゼ; 細胞内情報伝達; 心筋虚血再灌流; 細胞間接着分子; 抗体治療; CD54(ICAM-1); CD6

In response to hypoxia and reoxygenation, mammalian cells are known to express a variety of genes to adapt to these external stresses or lead to further cell damage. The intracellular signaling cascades in cultured rat cardiac myocytes subjected to hypoxia or hypoxia followed by reoxygenation (hypoxia/reoxygenation) were investigated. We showed that both hypoxia and hypoxia/reoxygenation cause rapid activation of the mitogen-activated protein kinase kinase kinase (MAPKKK) activity of Raf-1. The activation was followed by the sequential activation of mitogen-activated protein kinase kinase (MAPKK), mitogen-activated protein (MAP) kinases, and S6 kinase (p90^<rsk>). Furthermore, hypoxia caused hyperphosphorylation of Raf-1. The maximal hyperphosphorylation of Raf-1 appeared to be accompanied by a significant decrease in MAPKKK activity. These results strongly suggest the following : (1) intracellular signals initiated by both hypoxia and hypoxia/reoxygenation converge on Raf-1, which sequentially activates downstream serine/threonine kinases including MAPKK,MAP kinases, and p90^<rsk>, (2) Raf-1 is not only located upstream from MAPKK and MAP kinases but also may be phosphorylated by MAP kinases directly or indirectly, and at least Raf-1 kinase activity may be downregulated by this feedback mechanism.

在对缺氧和再氧合的反应中，已知哺乳动物细胞表达多种基因以适应这些外部应激或导致进一步的细胞损伤。本文研究了培养的大鼠心肌细胞在缺氧或缺氧复氧（缺氧/复氧）条件下的细胞内信号级联反应。我们发现，缺氧和缺氧/复氧引起Raf-1的丝裂原活化蛋白激酶激酶（MAPKKK）活性的快速激活。活化之后依次活化丝裂原活化蛋白激酶激酶（MAPKK）、丝裂原活化蛋白（MAP）激酶和S6激酶（p90<rsk>）。此外，缺氧引起Raf-1的过度磷酸化。Raf-1的最大过度磷酸化似乎伴随着MAPKKK活性的显著降低。这些结果有力地表明：（1）由缺氧和缺氧/复氧引发的细胞内信号会聚于Raf-1，Raf-1依次激活下游的丝氨酸/苏氨酸激酶，包括MAPKK、MAP激酶和p90 α<rsk>;（2）Raf-1不仅位于MAPKK和MAP激酶的上游，而且可以被MAP激酶直接或间接磷酸化，并且至少Raf-1激酶活性可通过该反馈机制下调。

项目成果

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Y. Seko 等人：“急性心肌病和扩张型心肌病患者感染细胞中 T 细胞受体 Vα-Vβ 基因的限制使用”，《临床研究杂志》96。1035-1041（1995 年）。

T.Yamazaki et.al: "Mechavical Loading Activates Mitogen-activated Protein Kinase and S6 Peptide Kinase in Cultured Rat Cardiac Myocytes" The Journal of Biological Chemistry. 268. 12069-12076 (1993)

T.Yamazaki 等人：“机械负荷激活培养的大鼠心肌细胞中的丝裂原激活蛋白激酶和 S6 肽激酶”《生物化学杂志》。

Y.Seko et.al: "Hypoxia and Hypoxia / Reoxygenation Activates R_<10>/-1, Mitogen-Activated Kinase Kinase, Mitogen-Activated Protein Kinases, and S6 Kinase in Cultured Rat Cardiac Myoaytes." Circulation Research. 96. 438-446 (1995)

Y.Seko 等人：“缺氧和缺氧/复氧激活培养的大鼠心肌细胞中的 R_10>/-1、丝裂原激活激酶、丝裂原激活蛋白激酶和 S6 激酶。”

M.Isobe et.al.: "Scintigraphic cletection of early cardiac rejection by iodine 123-labeled monoclonal antibody directed against,monomorplic determinant of major histocompatibility complex class II antigens." American Heat of Journal. 127(5). 1309-1317 (19

M.Isobe 等人：“通过针对主要组织相容性复合物 II 类抗原的单形决定簇的碘 123 标记单克隆抗体对早期心脏排斥进行闪烁照相检测。”

I.Komuro,Y.Yazaki: "control of cardiac gene expression by mechanical stress." Annu.Rev.Physiol.55. 55-75 (1993)

I.Komuro，Y.Yazaki：“机械应力控制心脏基因表达。”