2007 Fiscal Year Final Research Report Summary
Translational Research of-Heparin Cofactor II for Athemsderosis Prevention
| Project/Area Number |
18590816
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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 | The University of Tokushima |
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Principal Investigator |
AIHARA Kenichi The University of Tokushima, Institute of Health Biosciences, Graduate School, associate professor (70372711)
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| Co-Investigator(Kenkyū-buntansha) |
AKAIKE Masashi The University of Tokushima, Institute of Health Biosciences, Graduate School, associate professor (90271080)
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| Project Period (FY) |
2006 – 2007
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| Keywords | heparin cofactor II(HCII) / knockout mice / embryonic lethality / vascular remodeling / thrombosis / thrombin |
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| Research Abstract |
Heparin cofactor II (HCII) specifically inhibits thrombin action at sites of injured arterial wall, and patients with HCII deficiency exhibit advanced atherosclerosis. However, the in vivo effects and the molecular mechanism underlying the action of HCII during vascular remodeling remain elusive. To clarify the role of HCII in vascular remodeling, we generated HCII-deficient mice by gene targeting. In contrast to a previous report, HCII (-/-) mice were embryonically lethal. In HCII (+/-) mice, prominent intimal hyperplasia with increased cellular proliferation was observed after tube cuff and wire vascular injury. The number of protease-activated receptor-l-positive (PAR-1-positive) cells was increased in the thickened vascular wall of HCII (+/-) mice, suggesting enhanced thrombin action in this region. Cuff injury also increased the expression levels of inflammatory cytokines and chemokines in the vascular wall of HCII (+/-) mice. The intimal hyperplasia in HCII (+/-) mice with vascular injury was abrogated by human HCII supplementation. Furthermore, HCII deficiency caused acceleration of aortic plaque formation with increased PAR-1 expression and oxidative stress in apoE-KO mice. These results demonstrate that HCII protects against thrombin-induced remodeling of an injured vascular wall by inhibiting thrombin action and suggest that HCII is potentially therapeutic against atherosclerosis without causing coagulatory disturbance.
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