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Novel regulatory mechanism of vascular endothelial function mediated by BMK1/ERK5 and its application for anti-atherosclerosis therapy

BMK1/ERK5介导的血管内皮功能调控新机制及其在抗动脉粥样硬化治疗中的应用

基本信息

批准号：
17590740
负责人：
AKAIKE Masashi
金额：
$ 2.18万
依托单位：
The University of Tokushima
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590740/
关键词：
BMK1 ERK5 vascular endothelial function statin KLF2 inflammation nitric oxide synthase pleiotropic effect atherosclerosis PPARγ VCAM-1

项目摘要

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.

利用表达Gal-DNA结合域与BMK 1/ERK 5融合蛋白的哺乳动物表达载体，建立了双荧光素酶报告基因检测BMK 1/ERK 5活性的定量检测体系。匹伐他汀可剂量依赖性地增强血管内皮细胞BMK 1/ERK 5活性。匹伐他汀诱导的BMK 1/ERK 5激活被认为是他汀类药物的类效应，因为其他他汀类药物，阿托伐他汀和辛伐他汀，也激活BMK 1/ERK 5。给予胆固醇生物合成中的类异戊二烯中间体之一香叶基香叶基焦磷酸（GGPP）可消除匹伐他汀的作用。以往的研究表明，抑制GGPP的合成可通过抑制Rho激酶而产生多效性效应。然而，由于Rho激酶抑制剂Y27632不能激活BMK 1/ERK 5，因此BMK 1/ERK 5的激活被认为是一种新的不依赖于Rho激酶的血管内皮功能调节系统。匹伐他汀可降低TNFα诱导的VCAM-1表达，但通过转染显性失活的MEK 5 β抑制BMK 1/ERK 5可消除这种抗炎作用。此外，匹伐他汀诱导的eNOS启动子活性的增加几乎被BMK 1/ERK 5 siRNA转染所消除。我们报道匹伐他汀增强了PPARγ1的转录活性，BMK 1/ERK 5与PPARγ1结合，从而激活其活性。最近的研究表明，剪切应力通过增加KLF 2的表达来增强eNOS启动子的活性。这些结果表明，他汀类药物诱导的BMK 1/ERK 5激活通过激活PPARγ1抑制粘附分子表达和通过KLF 2表达增加eNOS表达，在调节血管内皮功能中起重要作用。