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

• 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
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16209027/
• 关键词: Endothelium-derived relaxing factors; Endothelium-derived hyperpolarizing factor; Hydrogen peroxide; Nitric oxide; Atherosclerosis; Cardiovascular diseases; Rho-kinase; Microcirculation; 内皮由来過分極因子(EDHF); 内皮由来弛緩因子; 内皮型NO合成酵素(eNOS); NOS欠損マウス; eN

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合酶系统在EDHF/H_2_O2生成中的作用(1)我们已经证明内皮细胞Cu,Zn-SOD不仅在动物中而且在人类中在EDHF/H_2O_2的合成中起着重要作用。(2 ）我们已经证明，长期抑制 Rho 激酶（可下调 eNOS）可改善各种心血管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)在那些三重NOSs-KO小鼠中，EDHF反应被消除，证明了内皮NOSs系统在EDHF/H_2O_2的合成中的重要性。2.H_2O_2的生理和病理机制合成(1)我们能够证明内皮细胞在下午顺序释放H_2O_2和NO，并且这两种物质(2)我们已经证明其他内皮氧化酶系统(例如NADPH)不参与EDHF/H_2O_2反应。3.H_2O_2的体内成像我们能够证明内皮细胞的产生4. EDHF/H_2O_2 在动物体内的作用我们已经证明了EDHF/H_2O_2在心肌缺血/再灌注和代谢性冠状动脉舒张中也发挥着重要的保护作用。5.EDHF/H_2O_2在人体中的作用(1)我们已经证明，在培养的人冠状动脉血管平滑肌细胞中，雌激素下调调节，而尼古丁上调 Rho-激酶。(2)我们已经证明，选择性 Rho-激酶抑制剂可急剧减少肺血管肺动脉高压患者的阻力没有全身血流动力学影响。

项目成果

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

• 发表时间: 2006
• 期刊: 日本臨床 64
• 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。

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

Upregulated neuronal nitric oxide synthase compensates coronary flow response to bradykinin in endothelial nitric oxide-deficient mice.

上调的神经元一氧化氮合酶补偿了内皮一氧化氮缺陷小鼠的冠状动脉血流对缓激肽的反应。

• 发表时间: 2004
• 期刊: Journal of Cardiovascular Pharmacology 44
• 作者: Talukder MAH;Shimokawa H;et al.
• 通讯作者: et al.

Endothelial nitric oxide synthase-independent effect of an ACE inhibitor on coronary flow response to bradykinin in mice.

ACE 抑制剂对小鼠缓激肽冠脉血流反应的内皮一氧化氮合酶独立作用。

• 发表时间: 2004
• 期刊: Journal of Cardiovascular Pharmacology 44
• 作者: Talukder MAH;Shimokawa H;et al.
• 通讯作者: et al.

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

• 发表时间: 2006
• 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