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Relationship between mitochondrial ATP sensitive potassium channels and reactive oxygen species in cardiovascular tissue.

线粒体 ATP 敏感钾通道与心血管组织中活性氧的关系。

基本信息

批准号：
15590230
负责人：
KIMURA Shoji
金额：
$ 2.37万
依托单位：
Kagawa University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

This study aimed to examine the involvement of mitochondria-derived reactive oxygen species (ROS) in the signaling pathway and the vasoconstrictor mechanism of Ang II. Using 5-hydroxydecanoate (5-HD ; a specific inhibitor of mitochondrial ATP-sensitive potassium channels (mitoKATP)) and tempol (a superoxide dismutase mimetic), the effects of Ang II and diazoxide (a mitoKATP opener), were compared on redox-sensitive mitogen-activated protein kinase (MAPK) activation in rat vascular smooth muscle cells (RVSMC) in vitro and in rat aorta in vivo. Stimulation of RVSMC by Ang II or diazoxide increased phosphorylated MAPK (ERK1/2,p38 and JNK) as well as superoxide production ; which were then suppressed by 5-HD pretreatment in a dose dependent manner, except for ERK1/2 activation by Ang II. The same events were reproduced in rat aorta in vivo. Ang II like diazoxide depolarized the mitochondrial membrane potential (ΔΨ_M) of RVSMC, which was inhibited by 5-HD. 5-HD did not modulate Ang II induc … More ed calcium mobilization in RVSMC and did not affect on the vasoconstrictor effect in either acute or chronic phases of Ang II induced hypertension. These results reveal that Ang II stimulates mitochondrial ROS production through the opening of mitoKATP in the vasculature, leading to reduction of ΔΨ_M and redox-sensitive activation of MAPK ; however, generated ROS from mitochondria do not contribute to Ang II-induced vasoconstriction. See Hypertension 2005;45(3):438-44 and Hypertension 2005 (in press) in detail. The related articles also demonstrated as shown below ;1)Acute administration of Ang II and phenylephrine to conscious rats provoked redox-sensitive activation of MAPK in the heart and aorta. (Hypertension. 2004;43:117-24, J Pharmacol Sci. 2004;96;406-10)2)The mechanisms of Ang II induced vasoconstriction may shift from being non-sensitive to ROS to sensitive within 12 hours. (J Hypertens. 2004;22:2161-8.)3)(β-adrenoceptor stimulation provokes cardiac oxidative stress, while the generated ROS are responsible for the activation of MAPK cascade. (Cardiovasc Res. 2005;65:230-8.) Less

本研究旨在探讨血管紧张素Ⅱ（Ang Ⅱ）信号通路中活性氧（ROS）的参与及其缩血管机制。应用线粒体ATP敏感性钾通道（mitoKATP）特异性抑制剂5-羟基癸酸（5-HD）和超氧化物歧化酶模拟物tempol，比较了血管紧张素Ⅱ（Ang Ⅱ）和mitoKATP开放剂二氮嗪（diazoxide）对体外大鼠血管平滑肌细胞（RVSMC）和体内大鼠主动脉氧化还原敏感性丝裂原活化蛋白激酶（MAPK）激活的影响。Ang II或二氮嗪刺激RVSMC增加磷酸化MAPK（ERK 1/2，p38和JNK）以及超氧化物的产生，然后抑制5-HD预处理以剂量依赖性的方式，除了ERK 1/2激活的Ang II。同样的事件在大鼠体内主动脉中再现。Ang Ⅱ样二氮嗪使RVSMC线粒体膜电位（Δ M）去极化，5-HD可抑制Δ M的去极化。5-HD不调节Ang II诱导的细胞凋亡。 ...更多信息艾德能增加RVSMC钙的动员，但不影响Ang Ⅱ诱导的急性或慢性期的血管收缩作用。这些结果表明，Ang II通过开放血管系统中的mitoKATP刺激线粒体ROS产生，导致Δ Δ KATP_M减少和MAPK的氧化还原敏感性激活;然而，来自线粒体的ROS不有助于Ang II诱导的血管收缩。详见Hypertension 2005;45（3）：438-44和Hypertension 2005（in press）。相关文献也证明如下：1）清醒大鼠急性给予Ang II和苯肾上腺素可引起心脏和主动脉中MAPK的氧化还原敏感性激活。（高血压。2004;43：117-24，J Pharmacol Sci. 2004;96;406-10）2）Ang II诱导的血管收缩的机制可以在12小时内从对ROS不敏感转变为敏感。（J Hypertens. 2004;22：2161-8.）3）（β-肾上腺素受体刺激引起心脏氧化应激，而产生的活性氧则负责激活丝裂原活化蛋白激酶级联反应。（2005年《生物化学研究》;65：230- 238）少

项目成果

期刊论文数量（42）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of ATI receptor blockade on renal injury and mitogen-activated protein kinase activity in Dahl salt-sensitive rats.

ATI 受体阻断对 Dahl 盐敏感大鼠肾损伤和丝裂原激活蛋白激酶活性的影响。

DOI：
发表时间：
2004
期刊：
Kidney Int. 65
影响因子：
0
作者：
Zhang GX.et al.;Fujisawa Y.et al.;Nishiyama A.et al.;Nishiyama A.et al.;Rahman M.et al.;Nishiyama A.et al.
通讯作者：
Nishiyama A.et al.

Role of angiotensin II and reactive oxygen species in cyclosporine A-dependent hypertension