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Intracellular signal transduction via acitive oxygen production in cardiac myocytes-role of redox regulation in Mn-SOD induction-

通过心肌细胞活性氧产生的细胞内信号转导-氧化还原调节在Mn-SOD诱导中的作用-

基本信息

批准号：
10670652
负责人：
NISHIDA Masashi
金额：
$ 2.18万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 1999
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10670652/
关键词：
Mn-SOD Cardiac myocyte hydrogen peroxide oxidative stress cytokine TNF-α DCFH 細胞障害

项目摘要

To investigate the role of active oxygen/ oxygen radical metabolism in intracellular signal transduction of myocardial stress response, we examined the production of active oxygen species and the induction of stress proteins in activated cardiac myocytes and the relationship between these two phenomena. In the first year, we demonstrated that hydrogen peroxide was produced in cardiac myocytes stimulated with TNF-α using hydrogen peroxide sensitive dye, DCFH. TNF-α also augmented Mn-SOD expression in cardiac myocytes. Because 2-mercaptopropionyl glycine (MPG), which scavenge hydrogen peroxide, blocked Mn-SOD induction in cardiac myocytes by TNF-α hydrogen peroxide produced by TNF-α in cardiac myocytes directly linked to the expression of Mn-SOD. In the second year, we examined whether the induction of Mn-SOD in cardiac myocytes by TNF-α occurred in vivo. In treadmill exercise model of rat, concentration of TNFα and IL-1β in cardiac myocytes increased soon after exercise together with the augmentation of Mn-SOD protein and activity 48 hr after exercise. Antibody to TNFα and IL-1β attenuated the induction of Mn-SOD by exercise. MPG could also attenuated Mn-SOD induction by exercise. These results suggest that physical stress such as exercise produced cytokines in cardiac myocytes and the cytokines, thus produced, induced antioxidative enzyme, Mn-SOD, in myocardium through the activation of signal transduction pathway mediated by hydrogen peroxide.

为了探讨活性氧/氧自由基代谢在心肌细胞应激反应的细胞内信号转导中的作用，我们检测了激活心肌细胞中活性氧的产生和应激蛋白的诱导以及这两种现象之间的关系。在第一年，我们用过氧化氢敏感染料DCFH证明了TNF-α刺激心肌细胞产生过氧化氢。TNF-α还可增加心肌细胞Mn-SOD的表达。由于2-巯基丙酰甘氨酸（MPG）抑制过氧化氢，阻断TNF-α诱导心肌细胞Mn-SOD的活性，而TNF-α在心肌细胞产生的过氧化氢与Mn-SOD的表达直接相关。在第二年，我们检查了TNF-α是否在体内诱导心肌细胞中Mn-SOD。在大鼠跑台运动模型中，运动后即刻心肌细胞TNFα和IL-1β含量升高，运动后48 h Mn-SOD蛋白和活性增加。TNFα和IL-1β抗体可减弱运动对Mn-SOD的诱导作用。MPG还能减弱运动对Mn-SOD的诱导作用。这些结果表明，运动等物理应激可使心肌细胞产生细胞因子，这些细胞因子通过激活过氧化氢介导的信号转导途径，诱导心肌细胞产生抗氧化酶Mn-SOD。