2006 Fiscal Year Final Research Report Summary
Novel regulatory mechanism of vascular endothelial function mediated by BMK1/ERK5 and its application for anti-atherosclerosis therapy
| Project/Area Number |
17590740
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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 |
AKAIKE Masashi The University of Tokushima, Hospital, Assistant professor, 医学部・歯学部・附属病院, 講師 (90271080)
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| Co-Investigator(Kenkyū-buntansha) |
AZUMA Hiroyuki The University of Tokushima, Institute of Health Biosciences, Associated professor, 大学院ヘルスバイオサイエンス研究部, 助教授 (10241275)
AIHARA Ken-ichi The University of Tokushima, Institute of Health Biosciences, Instructor, 大学院ヘルスバイオサイエンス研究部, 助手 (70372711)
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| Project Period (FY) |
2005 – 2006
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| Keywords | BMK1 / ERK5 / vascular endothelial function / statin / KLF2 / inflammation / nitric oxide synthase / pleiotropic effect / atherosclerosis |
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| Research Abstract |
We established the quantitative measurement system of BMK1/ERK5 activity by dual-luciferase reporter gene assay using mammalian expression vector which expressed the fusion protein of Gal-DNA binding domain and BMK1/ERK5. Pitavastatin markedly enhanced BMK1/ERK5 activity in dose-dependent manner in cultured vascular endothelial cells. Pitavastatin-induced BMK1/ERK5 activation is thought to be the class effect of statin because other statins, atorvastatin and simvastatin, also activate BMK1/ERK5. The effect of pitavastatin is abolished by the administration of geranylgeranylpyrophosphate (GGPP), one of isoprenoid intermediates in cholesterol biosynthesis. Previous reports showed inhibition of GGPP synthesis causes pleiotropic effect via the inhibition of Rho kinase. However, activation of BMK1/ERK5 is thought to be a novel regulatory system of vascular endothelial function Rho kinase-independently because Y27632, Rho kinase inhibitor, can not activate BMK1/ERK5. Pitavastatin decreased TNFα-induced VCAM-1 expression, but the inhibition of BMK1/ERK5 by the transfection of dominant-negative MEK5β abolished the anti-inflammatory effect. In addition, pitavastatin-induced increase of eNOS promoter activity was almost abolished by transfection of BMK1/ERK5 siRNA. We reported that pitavastatin enhanced PPARγ1 transcriptional activity and that BMK1/ERK5 associated with PPARγ1, leading to activate its activity. Recent report showed that shear stress enhanced eNOS promoter activity via increased expression of KLF2. These finding suggested that statin-induced BMK1/ERK5 activation plays an important role for regulation of vascular endothelial function through the suppression of adhesion molecule expression via PPARγ1 activation and the increase of eNOS expression via KLF2 expression.
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