2005 Fiscal Year Final Research Report Summary
Mechanisms of arterial thrombogesis in acute coronary syndromes and development of cell adhesion molecule inhibitor
| Project/Area Number |
16590722
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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 | Kurume University |
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Principal Investigator |
IKEDA Hisao Kurume University, School of Medicine, 医学部, 教授 (50168134)
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| Co-Investigator(Kenkyū-buntansha) |
YOKOYAMA Shinji Kurume University, School of Medicine, 医学部, 助手 (10320194)
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| Project Period (FY) |
2004 – 2005
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| Keywords | thrombosis / platelet / leukocyte / P-selectin / P-selectin knock out mouse / Internal Medicine / Cardiology / cell and tissue |
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| Research Abstract |
BACKGROUND Plaque rupture followed by thrombus formation is a fundamental pathophysiology of acute coronary syndromes. Although the adhesive interaction between platelets and leukocytes via P-selectin is known to mediate platelet-rich thrombi, the true function of P-selectin in thrombus formation in vivo is unknown. We therefore investigated whether P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates. METHODS In wild-type(P^<+/+>) and P-selectin-deficient(P^<-/->)mice with ferric chloride-induced carotid arterial thrombosis model, we measured in vivo platelet P-selectin expression and ADP-induced ex vivo platelet aggregation. We also measured ex vivo ADP-induced whole blood aggregations and their size distribution by flow cytometry. RESULTS Time to thrombotic occlusion was longer in p^<-/-> mice than in P^<+/+> mice. Spontaneous reflow after total thrombotic occlusion was observed in 8 of 10 P^<-/-> mice but not in any P^<+/+> mice. ADP-induced ex vivo platelet aggregation was not different between both groups. However, ADP-induced ex vivo whole blood aggregation was inhibited in P^<-/-> mice compared to P^<+/+> mice. FeCl_3-application increased in vivo expressions of platelet P-selectin in P^<+/+> mice but not in P^<-/-> mice. The number of leukocytes within thrombi was less in P^<-/-> mice than in P^<+/+> mice. In flowcytometric analysis of size distribution of ADP-induced whole blood aggregates, the number of large aggregates was less in P^<-/-> mice than in P^<+/+> mice. Using platelet and leukocyte fluorescence makers, the large aggregates were confirmed as platelet-leukocyte aggregates. CONCLUSIONS Platelet P-selectin plays an important role in arterial thrombogenesis by forming large stable platelet-leukocyte aggregates.
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