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Physiological significance of big mitogen-activated protein kinase 1 in metabolic syndrome

大丝裂原激活蛋白激酶1在代谢综合征中的生理意义

基本信息

批准号：
18590238
负责人：
YOSHIZUMI Masanori
金额：
$ 2.57万
依托单位：
Nara Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18590238/
关键词：
MAP kinases Big MAP kinase 1 Metabolic Syndrome insulin resistance Diabetes Mellitus vascular injury TNF-α blood flow アンジオテンシンII 炎症

项目摘要

In the current research project, we investigated the physiological significance of big mitogen-activated protein kinase 1 in metabolic syndrome using the model animals of diabetic rats and cultured cells.1) In the type 2 diabetic rat model OLETF, BMK1 was activated in vascular smooth muscles of small arteries. Similar results were obtained in the atherosclerotic model mice at the site of adventitia of cuff-injured femoral artery. From these findings, it was suggested that BMK1 activation is involved in the pathogenesis of diabetic microangiopathy.2) In experiments using cultured rat aortic smooth muscle cells (RASMC), platelet-derived growth factor (PDGF) stimulated BMK1 activation in a time and concentration-dependent manner. SHP-2 and Gab1 exist upstream of BMK1 and were activated by PDGF stimulation. PDGF also stimulated RASMC migration, which was inhibited by a transfection with dominant-negative MEK5. These findings suggest that BMK1 is involved in the pathogenesis of inflammatory vascular remodeling.3) In experiments using human umbilical vein endothelial cells (HUVEC), laminar fluid shear stress stimulated BMK1 activation. TNF-α stimulates c-Jun N-terminal kinase (INK) activation, which was inhibited by laminar flow. Physiological significance of BMK1 in endothelial cells has also confirmed. From these in vivo and in vitro findings, BMK1 is suggested to be involved in vascular injury in metabolic syndrome and BMK1 may be one of the drug targets for treatment of metabolic syndrome.

本研究采用糖尿病大鼠模型和体外培养细胞，探讨大丝裂原活化蛋白激酶1在代谢综合征中的生理意义。1）在2型糖尿病大鼠模型OLETF中，BMK 1在小动脉平滑肌中被激活。在动脉粥样硬化模型小鼠股动脉套囊损伤的外膜部位也获得了类似的结果。2）在培养的大鼠主动脉平滑肌细胞（RASMC）实验中，血小板源性生长因子（PDGF）以时间和浓度依赖的方式刺激BMK 1的活化。SHP-2和Gab 1存在于BMK 1的上游，并被PDGF刺激激活。PDGF也刺激RASMC迁移，这是抑制转染显性阴性MEK 5。这些发现表明BMK 1参与炎症性血管重塑的发病机制。3）在使用人脐静脉内皮细胞（HUVEC）的实验中，层流剪切应力刺激BMK 1活化。TNF-α刺激c-Jun N-末端激酶（INK）活化，其被层流抑制。BMK 1在内皮细胞中的生理意义也得到了证实。从这些体内和体外的研究结果，BMK 1被认为是参与血管损伤的代谢综合征和BMK 1可能是一个药物靶点，用于治疗代谢综合征。