Grant-in-Aid for Scientific Research (A)
|Allocation Type||Single-year Grants |
Circulatory organs internal medicine
|Research Institution||Tohoku University (2005-2006)|
Kyushu University (2004)
SHIMOKAWA Hiroaki Tohoku University, Graduate School of Medicine, Professor, 大学院医学系研究科, 教授 (00235681)
TAKESHIGE Kouichirou Kyushu University, Faculty of Medical Sciences, Professor, 大学院医学研究院, 教授 (10037450)
UTSUMI Hideo Kyushu University, Faculty of Pharmaceutical Sciences, Professor, 大学院薬学研究院, 教授 (20101694)
AKAIKE Takaaki Kumamoto University, Faculty of Medical and Pharmaceutical Sciences, Associate Professcr, 大学院医学薬学研究部, 助教授 (20231798)
IBAYASHI Setsurou Kyushu University, Faculty of Medical Sciences, Associate Professor, 大学院医学研究院, 助教授 (40213201)
HIROOKA Yoshitaka Kyushu University, Hospital, Lectarer, 病院・講師 (90284497)
|Project Period (FY)
2004 – 2006
Completed (Fiscal Year 2006)
|Budget Amount *help
¥47,970,000 (Direct Cost: ¥36,900,000、Indirect Cost: ¥11,070,000)
Fiscal Year 2006: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2005: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2004: ¥20,670,000 (Direct Cost: ¥15,900,000、Indirect Cost: ¥4,770,000)
|Keywords||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 / eNOS欠損マウス|
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_2
We were able to demonstrate endothelial production of H_2O_2 using DCF fluorescence imaging in vivo.
4.Role of EDHF/H_2O_2 in animals
We 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.