| Project/Area Number |
14370038
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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 |
General pharmacology
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| Research Institution | Osaka Medical College |
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Principal Investigator |
MIYAZAKI Mizuo Osaka Medical College, Faculty of Medicine, Professor, 医学部, 教授 (10047186)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAI Shinji Osaka Medical College, Faculty of Medicine, Associate Professor, 医学部, 助教授 (80288703)
JIN Denan Osaka Medical College, Faculty of Medicine, Assistant Professor, 医学部, 講師 (90319533)
MURAMATSU Michiko Osaka Medical College, Faculty of Medicine, Research Associate, 医学部, 助手 (30330096)
岡本 由記子 大阪医科大学, 医学部, 助手 (10268188)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,300,000 (Direct Cost: ¥14,300,000)
Fiscal Year 2004: ¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2003: ¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2002: ¥8,000,000 (Direct Cost: ¥8,000,000)
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| Keywords | chymase / chymase inhibitor / myocardial infarction / cardiac function / aortic aneurysm / angiotensin II / angiotensin converting enzyme / angiotensin II receptor blocker / アンジオテンシンII |
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| Research Abstract |
In this report, we added new evidences that indicate the important roles of mast cell derived chymase in multiple cardiovascular diseases.
We showed already that angiotensin II produced by chymase makes substantial contribution in cardiovascular diseases.
In addition, we found newly that human chymase activates latent transforming growth factor (TGF) β to active TGF-β which is involved in cardiovascular fibrosis.
Chymase added into cultured human fibroblasts increased the TGF-β concentration and the number of cells. These effects were completely suppressed by chymase inhibitor or anti-TGF-β antibody. In hamsters with cardiomyopathy, a chymase activity was significantly increased and chymase inhibitor lowered the activity and collagen expression in the heart.
In myocardial infracted hamsters, chymase activity also increased in the heart but this increase was reduced by chymase inhibitor with prolongation of survival rate. In dog models, we confirmed that chymase inhibitor reduced remarkably the incidence of arrhythmia after the myocardial infarction.
In balloon injured model of the carotid artery of dogs, chymase but not angiotensin converting enzyme activity increase significantly in the injured vessel. Chymase inhibitor could prevent the increase of the enzyme and prevented the vascular proliferation. In the arteriovenous fistula model of dogs, chymase- and TGF β -positive mast cells were markedly accumulated in the proliferous neointima but the cell numbers were reduced by chymase inhibitor.
Our results elucidated the pathogenesis mechanism of chymase in various cardiovascular diseases and suggested that chymase and the development of chymase inhibitor is a new target for prevention of the diseases.
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