2000 Fiscal Year Final Research Report Summary
Pathophysiological roles of the anti-fibrinolytic factor PAI-1 during aging or apoptotic process of blood vessel
| Project/Area Number |
10672083
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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 |
Biological pharmacy
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| Research Institution | Fukuoka University |
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Principal Investigator |
SOEDA Shinji Fukuoka Univ. Fac. Pharm. Sci. Associate Professor, 薬学部, 助教授 (20078695)
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| Co-Investigator(Kenkyū-buntansha) |
SHIMENO Hiroshi Fukuoka Univ. Fac. Pharm. Sci. Professor, 薬学部, 教授 (00078693)
KOYANAGI Satoru Fukuoka Univ. Fac. Pharm. Sci. Research Associate, 薬学部, 助手 (60330932)
KIHARA Taro Fukuoka Univ. Fac. Pharm. Sci. Research Associate, 薬学部, 助手 (20289549)
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| Project Period (FY) |
1998 – 2000
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| Keywords | Vascular endothelial cells / Apoptosis / Ceramide / Fibrinolytic factors / Proteinase inhibitor / Angiogenesis / Neuronal cell death / Anti-apoptotic action |
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| Research Abstract |
Expression of anti-fibrinolytic factor, PAI-1, increases in viscerofat of adiposis patients, and the increased PAI-1 give rise to a risk for myocardial infarction. In this study, we indicate that ceramide signaling event underlies an increase in PAI-1 release from vascular endothelial cells (HUVEC). TNF-α activated sphingomyelinase present on the plasma membrane or lysosomes of HUVEC and increased the ceramide levels. The ceramide promoted the expression of PAI-1 mRNA via activation of JNK/SAPK pathway. HUVEC have another ceramide formation system, which synthesizes ceramide in microsomes or mitochondria by the condensation of sphingosine with acyl-CoA.When the synthesis of ceramide in HUVEC was increased with a drug, the de novo synthesized ceramide decreased the PAI-1 mRNA expression by down-regulation of JNK pathway. These results suggest that the subcellular topology of ceramide production determines its lipid mediator function in the regulation of PAI-1 synthesis. We also purified
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and characterized ceramide synthase from bovine liver mitochondria, since its properties are unknown.
Prevention of growing vessels in tumors is one of the new therapeutic strategies of cancer. Plasminogen activator-plasmin system plays an important role in angiogenesis. We demonstrate that a drug capable of increasing PAI-1 release from vascular endothelial cells may provide a therapeutic benefit for the prevention of tumor growth through inhibition of angiogenesis. We further investigated the role of PAI-lin brain and found that astrocytes had the ability to efficiently release PAI-1. Deficient release of PAI-1from astrocytes greatly affected the survival of neurons and led to the apoptotic cell death. The data suggest that neural PAI-1 has physiological functions other than its role as proteinase inhibitor. We searched compounds that have the ability to prevent apoptosis in neurons and found that a newly synthesized sphingomyelin analog and a saffron pigment, crocin, both had anti-apoptotic action to neuronal cells. Less
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