| Project/Area Number |
10670040
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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 |
General physiology
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| Research Institution | Hamamatsu University School of Medicine |
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Principal Investigator |
URANO Tetsumei Hamamatsu Univ.Sch. of Med., Dept. of Physiology, Associate Professor, 医学部, 助教授 (50193967)
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| Co-Investigator(Kenkyū-buntansha) |
IHARA Hayato Hamamatsu Univ, Sch. of Med., Dept. of Physiology, Assistant, 医学部, 助手 (00223298)
TAKADA Akikazu Hamamatsu Univ.Sch. of Med., Dept. of Physiology, Professor, 医学部, 教授 (80092980)
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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 |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Keywords | PAI-1 / thrombin / factor Xa / thrombomodulin / fibrinolysis / coagulation |
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| Research Abstract |
Total fibrinolytic activity in the vasculature is finely tuned by the balance between tissue plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI-1). Although PAI-1 targets PAs, it also reacts with other serine proteases such as thrombin and factor Xa. Such neutralization of PAI-1 activity by these activated coagulation factors was shown to be strongly involved in the coagulation-associated enhancement of fibrinolytic activity. The interaction between thrombin and PAI-1 was quenched by soluble thrombomodulin (TM), whose mature form exists on normal vascular endothelial cells and modifies thrombin's substrate specificity. As a result, soluble TM quenched the shortening of t-PA-induced fibrin clot lysis time obtained by thrombin-dependent PAI-1 neutralization. We have also shown that the shortening of euglobulin clot lysis time (ECLT) by Ca^<++> and phospholipid was also induced by the neutralization of PAI-1 activity by Ca^<++>-bound factor Xa and thrombin. This Ca^<++>-dependent shortening of ECLT was also partially quenched by soluble TM.Coagulation associated enhancement of fibrinolysis due to PAI-1 neutralization by activated coagulation factors seems to take place on the growing thrombus where coagulation factors are continuously activated, whereas it does not take place on intact vascular endothelial cells where thrombomodulin is expressed. This mechanism seems to play an important role to control the sequential events of the formation, maintenance and dissolution of thrombus. This is also involved in the pathogenesis of elevated fibrinolytic activity in disseminated intravascular coagulation.
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