| Project/Area Number |
13670770
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | KURUME UNIVERSITY |
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Principal Investigator |
MATSUOKA Hidehiro Kurume University School of Medicine, Department of Internal Medicine III, Assistant Professor, 医学部, 講師 (80248393)
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| Co-Investigator(Kenkyū-buntansha) |
SUGANO Ryo Kurume University School of Medicine, Department of Internal Medicine III, Lecturer, 医学部, 助手 (80330819)
HARAMAKI Nobuya Kurume University School of Medicine, Department of Internal Medicine III, Assistant Professor, 医学部, 講師 (90248352)
IKEDA Hisao Kurume University School of Medicine, Department of Internal Medicine III, Associate Professor, 医学部, 助教授 (50168134)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥4,100,000 (Direct Cost: ¥4,100,000)
Fiscal Year 2002: ¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 2001: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | Atherosclerosis / Endothelium / Oxidative Stress / Inflammatory Cells / Hyperlipidemia / Statin / Risk Factor / Nitric Oxide / 冠危険因子 / レジン |
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| Research Abstract |
Atherosclerosis is considered as a systemic inflammatory process. Although lipid lowering therapies restore endothelial function partly through hsp90-mediated phosphorylation of endothelial nitric synthase in hypercholesterolemic models, precise mechanisms remain to be elucidated. In the present in vivo and ex vivo studies, we investigated a possible link between polymorphonuclear leukocytes (PMN) and endothelial function and the effects of lipid lowering therapies. In the first part of study, hypercholesterolemic subjects without other coronary risk factors were randomized to have fluvastatin or colestimide in a crossover design. Three months administration of fluvastatin or colestimide lowered LDL in a similar manner (p=.0001 for both). Endothelial function, estimated by flow-mediated vasodilation of the brachial artery, was restored only in fluvastatin-treated subjects (p=.0001). Similarly, fluvastatin improved the susceptibility of LDL to oxidation (p=.007) and attenuated superoxide release from PMN (p=.001), whereas colestimide had no effects on either lipid peroxidation or inflammatory cell activity. In the second part of ex vivo study, western blot analysis revealed that the exposure of PMN obtained from hypercholesterolemic subjects impaired the phosphorylation of nitric oxide synthase (eNOS) in cultured endothelial cells, whereas chronic fluvastatin treatment normalized eNOS phospholylation (p=.01). Thus, statin improved endothelial function by its anti-inflammatory properties, independent of LDL reduction. Our results raise a novel concept that circulating PMN, which burst a large amount of superoxide, may directly attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis.
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