| Project/Area Number |
14370227
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Kobe University |
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Principal Investigator |
YOKOYAMA Mitsuhiro Kobe University, Graduate School of Medicine Division of Cardiovascular and Respiratory Medicine, M.D.Professor, 大学院・医学系研究科, 教授 (40135794)
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| Co-Investigator(Kenkyū-buntansha) |
INOUE Nobutaka Kobe University, Graduate School of Medicine Division of Cardiovascular and Respiratory Medicine, M.D.Assistant Professor, 大学院・医学系研究科, 助手 (10304099)
KAWASHIMA Seinosuke Kobe University, Graduate School of Medicine Division of Cardiovascular and Respiratory Medicine, M.D.Associate Professor, 大学院・医学系研究科, 助教授 (10177678)
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| Project Period (FY) |
2002 – 2003
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| Project Status |
Completed (Fiscal Year 2003)
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| Budget Amount *help |
¥13,500,000 (Direct Cost: ¥13,500,000)
Fiscal Year 2003: ¥6,400,000 (Direct Cost: ¥6,400,000)
Fiscal Year 2002: ¥7,100,000 (Direct Cost: ¥7,100,000)
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| Keywords | endothelial nitric oxide synthase / nitric oxide / superoxide / atherosclerosis / tetrahydrobiopterin / gene-engineered mice / ジヒドロビオプテリン / GTPCH 1 / スパーオキシド / BH4 / apoE遺伝子欠損マウス |
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| Research Abstract |
NO from the endothelial NO synthase (eNOS) is believed to act as anti-atherogenic molecule. Indeed recent studies in eNOS gene-deficient mice showed the accelerated atherosclerotic lesion formation in mice that lacks eNOS gene. On the other hand, it is revealed that eNOS becomes dysfunctional and produces superoxide rather than NO under conditions in which tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, is lacking or deficient for eNOS enzymatic activity. This phenomenon is called eNOS uncoupling. In the present study we examined how eNOS overexpression affects atherogenesis under hypercholesterolemia. We crossed apo E-knockout mice (apo E-KO) with eNOS transgenic mice that overexpress eNOS in the endothelium (eNOS-Tg). We found that under hypercholesterolemia superoxide production was increased and NO production was relatively low in the aortas from apo E-KO/eNOS-Tg compared with those from apo E-KO. Therefore the presence of eNOS uncoupling was suggested in apo E-KO/eNOS-Tg. We also revealed that eNOS overexpression accelerated atherosclerotic lesion formation in apo E-KO. Vascular levels of BH4 were decreased in apo E-KO/eNOS-Tg compared with apo E-KO. Chronic treatment of apo E-KO/eNOS-Tg with exogenous BH4 decreased superoxide production and increased NO production from aortas, and reduced the atherosclerotic lesion area. Further overexpression of GTPCH 1, the rate limiting enzyme of BH4 synthesis, by crossing with GTPCH 1 transgenic mice also decreased atherosclerotic lesion area in apo E-KO/eNOS-Tg. Therefore, it seems that there is a minute balance between BH4 levels and eNOS protein levels in vascular tissue. When BH4 levels decrease under hypercholesterlemia, eNOS becomes uncoupling and produces superoxide rather than NO, which serves to accelerate atherogenesis.
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