| Project/Area Number |
06672219
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Biological pharmacy
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| Research Institution | Fukuoka University |
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Principal Investigator |
SOEDA Shinji Fukuoka University, Faculty of Pharmaceutical Sciences, Research Associa, 薬学部, 助手 (20078695)
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| Co-Investigator(Kenkyū-buntansha) |
NAGAMATSU Atsuo Fukuoka University, Faculty of Pharmaceutical Sciences, Profess, 薬学部, 教授 (70078682)
SHIMENO Hiroshi Fukuoka University, Faculty of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00078693)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥1,900,000 (Direct Cost: ¥1,900,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥1,100,000 (Direct Cost: ¥1,100,000)
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| Keywords | Vascular endothelium / Injurious factor / Antithrombus / Fibrinolytic factor / Sulfated polysaccharide / Ceramide / Second messenger / Endotoxin / 傷害因子 |
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| Research Abstract |
Vascular endothelial dysfunction underlies the initiation and progresssion of atherosclerosis and thrombosis. The objective of this study is to elucidate the nature of the dysfunctional changes in the endotheium. We investigated the roles of 15-HPETE,an arachidonate lipoxygenase product, in the atherosclerotic process. The results indicate that the activation of leukocytes and the release of 15-HPETE observed in the early step of atherosclerosis may cause lipid peroxidation of the endothelial membranes. The 15-HPETE-induced lipid peroxidation decreased the binding of antithrombotic factors to the cell surfaces in vitro. Also, 15-HPETE decreased the release of the fibrinolytic factor t-PA from vascular endothelial cells with increasing the release of its inhibitor PAI-1. These results suggest that the action of 15-HPETE to vascular endothelial cells enhances the risk of thrombosis by inducing both hypofibrinolysis and prothrombotic surfaces. 15-HPETE may act both on the membranes and within the cells, where some alteration in signal transduction pathway (s) that leads to the increased level of PAI-1 may occur. We found that the metabolic product of sphingomyelin, ceramide, acted as a lipid mediator of PAI-1 release from vascular endothelial cells. To better understand the regulatory mechanism of ceramide biosynthesis, we solubilized and partly characterized the ceramide synthase present in bovine brain mitochondria. We investigated the mechanism by which endotoxin enhances the release of PAI-1 from vascular endothelial cells, and found that heparan sulfate molecules were involved in the initial binding of endotoxin to vascular endothelial cells. Oversulfated fucoidan suppressed the endotoxin-induced PAI-1 release by inhibiting the binding of endotoxin to the cell surface heparan sulfate. We showed the in vivo antilipemic and antithrombotic activities of the fucoidan derivatives.
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