| Project/Area Number |
10670642
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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 | Hamamatsu University School of Medicine |
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Principal Investigator |
WATANABE Hiroshi Hamamatsu University School of Medicine, Clinical Pharmacology and Therapeutics, Associate Professor, 医学部, 助教授 (50262803)
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| Co-Investigator(Kenkyū-buntansha) |
TERADA Hajime Hamamatsu University School of Medicine, Internal Medicine III, Assistant Professor, 医学部, 助手 (50252177)
HAYASHI Hideharu Hamamatsu University School of Medicine, Internal Medicine III, Professor, 医学部, 教授 (50135258)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,000,000 (Direct Cost: ¥2,000,000)
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| Keywords | Myosin light chain kinase / Endothelial cell / Calcium / Nitric Oxide / Endothelium-derived hyperpolarizing factor / 一酸化窒素 / 内皮依存性過分極反応 / 内皮依存性血管拡張因子 |
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| Research Abstract |
Activation of smooth muscle myosin light-chain kinase (MLCK) causes contraction. Here we have proven that MLCK controls Ca^<2+> entry (CE) in endothelial cells (ECs) : MLCK antisense oligonucleotides strongly prevented bradykinin (BK)- and thapsigargin (TG)-induced endothelial Ca^<2+> response while MLCK sense did not. We also show that the relevant mechanism is not phosphorylation of myosin light-chain (MLC) : MLC phosphorylation by BK required CE, but MLC phosphorylation caused by the phosphatase inhibitor calyculin A did not trigger Ca^<2+> response. Most importantly, we provide for the first time strong evidence that, in contrast to its role in smooth muscle cells, activation of MLCK in ECs stimulates the production of important endothelium-derived vascular relaxing factors : MLCK antisense and MLCK inhibitors abolished BK- and TG-induced nitric oxide production, and MLCK inhibitors substantially inhibited acetylcholine-stimulated hyperpolarization of smooth muscle cell membrane in rat mesenteric artery. These results indicate that MLCK controls endothelial CE, but not through MLC phosphorylation, and unveil a hitherto unknown physiological function of the enzyme : vasodilation through its action in endothelial cells. The study discovers a counter-balancing role of MLCK in the regulation of vascular tone.
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