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Experimental and Clinical Studies on the Significance of Endothelium-Derived Hyperpolarizing Factor (EDHF)

内皮源性超极化因子（EDHF）意义的实验和临床研究

基本信息

批准号：
16209027
负责人：
SHIMOKAWA Hiroaki
金额：
$ 30.7万
依托单位：
Tohoku University (2005-2006)Kyushu University (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2006
项目状态：
已结题

项目摘要

1.Role of Endothelial NO synthases system in the production of EDHF/H_2_O2(1)We have demonstrated that endothelial Cu, Zn-SOD plays an important role in the synthesis of EDHF/H_2O_2 not only in animals but also in humans.(2)We have demonstrated that long-term inhibition of Rho-kinase, which down-regulates eNOS, ameliorates endothelial function in various animal models of cardiovascular diseases.(3)We have demonstrated that EDHF/H_2O_2 is involved in the effects of ACE inhibitors.(4)We have developed mice lacking all NO synthases. Those mice showed impaired survival with hypertension and myocardial infarction.(5)In those triply NOSs-KO mice, EDHF responses were abolished, demonstrating the importance of endothelial NOSs system in the synthesis of EDHF/H_2O_2.2.Mechanisms of Physiological and Pathological H_2O_2 Synthesis(1)We were able to demonstrate that endothelial cells release H_2O_2 and NO at p.M order and that the two factors interact synergistically to maintain coronary flow in dogs in vivo.(2)We have demonstrated that other endothelial oxidases system (e.g.NADPH) are not involved in the EDHF/H_2O_2 responses.3.In vivo imaging of H_2O_2We were able to demonstrate endothelial production of H_2O_2 using DCF fluorescence imaging in vivo.4.Role of EDHF/H_2O_2 in animalsWe have demonstrated that EDHF/H_2O_2 plays an important protective role in myocardial ischemia/reperfusion and metabolic coronary vasodilatation as well.5.Role of EDHF/H_2O_2 in humans(1)We have demonstrated that in cultured vascular smooth muscle cells from human coronary arteries, estrogen down-regulates while nicotine up-regulates Rho-kinase.(2)We have demonstrated that selective Rho-kinase inhibitors acutely reduces pulmonary vascular resistance without systemic hemodynamic effects in patients with pulmonary hypertension.

1.内皮NO合成酶系统在EDHF/H_2O_2合成中的作用(1)我们已经证明内皮Cu， Zn-SOD在动物和人体内EDHF/H_2O_2合成中起重要作用。(2)我们已经证明，长期抑制rho激酶可以下调eNOS，改善各种心血管疾病动物模型的内皮功能。(3)我们已经证明EDHF/H_2O_2参与了ACE抑制剂的作用。(4)我们培育了缺乏所有NO合酶的小鼠。这些小鼠表现出高血压和心肌梗死的生存受损。(5)在三重NOSs- ko小鼠中，EDHF反应被消除，表明内皮NOSs系统在EDHF/H_2O_2.2合成中的重要性。生理和病理H_2O_2合成机制(1)内皮细胞按pm顺序释放H_2O_2和NO，两者协同作用维持狗体内冠状动脉血流。(2)我们已经证明其他内皮氧化酶系统（如nadph）不参与EDHF/H_2O_2反应。H_2O_2的体内成像我们可以用DCF荧光成像在体内证明内皮细胞产生H_2O_2。EDHF/H_2O_2在动物中的作用我们已经证明EDHF/H_2O_2在心肌缺血/再灌注和代谢性冠状动脉血管扩张中也有重要的保护作用。EDHF/H_2O_2在人血管平滑肌细胞中的作用(1)我们已经证明，在培养的人冠状动脉血管平滑肌细胞中，雌激素下调rho激酶，而尼古丁上调rho激酶。(2)我们已经证明，选择性rho激酶抑制剂在肺动脉高压患者中急性降低肺血管阻力而不影响全身血流动力学。

项目成果

期刊论文数量（29）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

内皮由来過分極因子と内皮機能障害

内皮源性超极化因子和内皮功能障碍

DOI：
发表时间：
2006
期刊：
日本臨床 64
影响因子：
0
作者：
高木文;下川宏明
通讯作者：
下川宏明

Important role of hydrogen peroxide in pacing-induced metabolic coronary vasodilatation in dogs in vivo.

过氧化氢在狗体内起搏诱导的代谢性冠状血管舒张中的重要作用。

DOI：
发表时间：
2007
期刊：
Journal of the American College of Cardiolgy (in press)
影响因子：
0
作者：
Yada T;Shimokawa H;et al.
通讯作者：
et al.

Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo - A possible link between stress and coronary vasospasm

DOI：
10.1161/01.res.0000244093.69985.2f
发表时间：
2006-09-29
期刊：
CIRCULATION RESEARCH
影响因子：
20.1
作者：
Hizume, Takatoshi;Morikawa, Keiko;Shimokawa, Hiroaki
通讯作者：
Shimokawa, Hiroaki

内科学(第9版) 欠陥の収縮弛緩と血圧調節機構

内科学（第9版）收缩/舒张缺陷与血压调节机制

DOI：
发表时间：
2006
期刊：
影响因子：
0
作者：
Ishii K;Tamaoka A;Otsuka F;Iwasaki N;Shin K;Matsui A;Endo G;Kumagai Y;Ishii T;Shoji S;Ogata T;Ishizaki M;Doi M;Shimojo N.;石崎貴裕;Fukasawa M ed. al.;下川宏明
通讯作者：
下川宏明

Endothelium-derived hydrogen peroxide accounts for the enhancing effect of an angiotensin converting enzyme inhibitor on EDHF-mediated responses in mice.

内皮衍生的过氧化氢解释了血管紧张素转换酶抑制剂对小鼠 EDHF 介导的反应的增强作用。