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Investigation of the pathophysiological significance of big mitogen-activated protein kinase 1 in diabetic microangiopathy for the development of molecular-targeted drugs

大丝裂原激活蛋白激酶1在糖尿病微血管病变中的病理生理学意义研究对分子靶向药物开发的意义

基本信息

批准号：
16590195
负责人：
YOSHIZUMI Masanori
金额：
$ 2.3万
依托单位：
Nara Medical University (2005)The University of Tokushima (2004)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16590195/
关键词：
MAP kinases Big MAP kinase 1 Diabetic microangiopathy OLETF rat Cuff-injury Platelet derived growth factor SHP-2 Gab1

项目摘要

In the current research project, we investigated the pathophysiological significance of big mitogen-activated protein kinase 1 in diabetic microangiopathy for the development of molecular-targeted drugs.1)In the type 2 diabetic rat model OLETF, BMK1 was activated in the small artery at 30 weeks of age without apparent complications with diabetes mellitus. From these findings, it was suggested that BMK1 activation is involved in the pathogenesis of diabetic microangiopathy.2)In the mouse model of inflammatory vascular disease, big mitogen-activated protein kinase 1 (BMK1) was activated at the site of adventitia of cuff-injured femoral artery. At the site of cuff-injured artery, neointimal formation and infiltration of mononuclear cells were observed. These findings suggest that BMK1 is involved in the pathogenesis of inflammatory vascular remodeling.3)In experiments using cultured rat aortic smooth muscle cells (RASMC), aldosterone stimulated BMK1 activation. BMK1 activation by aldosterone was inhibited by treatment with eplerenone, a mineralocorticoid receptor blocker. Aldosterone-induced RASMC proliferation was inhibited by genetic BMK1 inhibition.4)In RASMC PDGF stimulated BMK1 activation in a time and concentration-dependent manner. PDGF also stimulated RASMC migration, which was inhibited by a transfection with dominant-negative MEK5.From these in vivo and in vitro findings, BMK1 is suggested to be involved in diabetic microangiopathy and BMK1 may be one of the drug targets for treatment of complications with diabetes mellitus.

本研究旨在探讨大丝裂原活化蛋白激酶1在糖尿病微血管病变中的病理生理学意义，为分子靶向药物的开发提供理论依据。1）在2型糖尿病大鼠模型OLETF中，30周龄时BMK 1在小动脉中被激活，无明显糖尿病并发症。结论：1）糖尿病微血管病变的发病机制可能与BMK 1的激活有关。2）炎症性血管病变小鼠模型中，大丝裂原活化蛋白激酶1（big mitogen-activated protein kinase 1，BMK 1）在袖套损伤的股动脉外膜处被激活。在袖套损伤的动脉部位，观察到新生内膜形成和单核细胞浸润。这些发现表明BMK 1参与炎症性血管重塑的发病机制。3）在使用培养的大鼠主动脉平滑肌细胞（RASMC）的实验中，醛固酮刺激BMK 1活化。醛固酮对BMK 1的激活作用可被盐皮质激素受体阻滞剂依普利酮抑制。醛固酮诱导的RASMC增殖可被BMK 1基因抑制所抑制。4）在RASMC中，PDGF以时间和浓度依赖的方式刺激BMK 1的激活。PDGF还能刺激RASMC迁移，而转染显性阴性的MEK 5则可抑制这种迁移。从体内外实验结果来看，BMK 1可能参与了糖尿病微血管病变的发生，BMK 1可能成为治疗糖尿病并发症的药物靶点之一。

项目成果

期刊论文数量（62）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Src and Cas are essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cells via ERK1/2 and JNK activation

Src 和 Cas 通过 ERK1/2 和 JNK 激活本质上但有区别地参与血管紧张素 II 刺激的血管平滑肌细胞迁移

DOI：
发表时间：
2004
期刊：
Mol.Pharmacol. 65,(4)
影响因子：
0
作者：
Matsuoka I;Tang Y;Ono T;Kimura J;杉浦麗子;Kyaw M ほか
通讯作者：
Kyaw M ほか

Ebselen inhibits tumor necrosis factor- α -induced c-Jun N-terminal kinase activation and adhesion molecule expression in endothelial cells.

Ebselen 抑制肿瘤坏死因子-α 诱导的 c-Jun N 末端激酶激活和内皮细胞中粘附分子的表达。

DOI：
发表时间：
2004
期刊：
Exp Cell Res 292
影响因子：
0
作者：
Yoshizumi M;Sone S;et al.
通讯作者：
et al.

ERK1/2 activation by angiotensin II inhibits insulin-induced glucose uptake in vascular smooth muscle cells

DOI：
10.1016/j.yexcr.2005.04.028
发表时间：
2005-08-15
期刊：
EXPERIMENTAL CELL RESEARCH
影响因子：
3.7
作者：
Izawa, Y;Yoshizumi, M;Tamaki, T
通讯作者：
Tamaki, T

Src and Cas essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cells via ERK1/2 and JNK activation.

Src 和 Cas 通过 ERK1/2 和 JNK 激活本质上但不同地参与血管紧张素 II 刺激的血管平滑肌细胞迁移。

DOI：
发表时间：
2004
期刊：
Mol.Pharmacol. 65(4)
影响因子：
0
作者：
Ohkawara H;Ishibashi T;Sakamoto T;Sugimoto K;Nagata K;Yokoyama K;Sakamoto N;Kamioka M;Matsuoka I;Fukuhara S;Sugimoto N;Takuwa Y;Maruyama Y;Reiko Sugiura;Lu Deng;Nishiyama A et al.;Nishiyama A et al.;Chika Sakamoto;Kyaw M et al.
通讯作者：
Kyaw M et al.

Transactivation of fetal liver kinase-1/kinase-insert domain-containing receptor by lysophosphatidylcholine induces vascular endothelial cell proliferation.

溶血磷脂酰胆碱反式激活胎儿肝激酶-1/激酶插入结构域受体可诱导血管内皮细胞增殖。