Activation of MAP Kinases and role in cardiovascular diseases - in vivo study -

MAP 激酶的激活及其在心血管疾病中的作用 - 体内研究 -

基本信息

批准号：
09670101
负责人：
MITSUYAMA Shokei
金额：
$ 1.73万
依托单位：
OSAKA CITY UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09670101/
关键词：
MAP Kinase ballon injury hypertension angiotensin vascular thickening cardiac hypertrophy 細胞増殖転写因子

项目摘要

Extracellular signal-regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK), which belong to mitogen-activated protein kinases (MAPK), play a key role in the regulation of cell growth or apoptosis, or various gene expressions. In spite of the critical importance of MAPK for cell function in vitro, the role of MAPK in the pathophysiology of cardiovascular system in vivo is poorly understood. We have examined the activities of MAPK in various cardiovascular disease models. JNK activity is chronically enhanced in cardiac hypertrophy of hypertensive rats or angiotensin II-infused rats, which is followed by the increase in activator protein-1 (AP-1) activity. Cardiac increased JNK activitiy is associated with the development of cardiac hypertrophy, suggesting the role of JNK in cardiac hypertrophy. In chronic hypertensive rats, vascular ERK and JNK activities are continuously increased compared with normotensive rats, with the development of vascular thickening. Furthermore, balloon injury rapidly and transiently activates vascular ERK and JNK, followed by the activation of AP-1. This activation of ERK and JNK in injured artery is in part blocked by AT1 receptor antagonist, indicating the contribution of AT1 receptor in ERK and JNK activation in injured artery. In vivo gene transfer of dominant interfering mutants of ERK or JNK prevents vascular neointima formation after balloon injury. Thus, the enhanced activation of JNK or ERK occurs in various cardiovascular disease models, supporting the notion that MAPK may be important for cardiovascular hypertrophy and remodeling.

细胞外信号调节激酶（ERK）和c-jun NH2末端激酶（JNK）属于丝裂原激活蛋白激酶（MAPK），在细胞生长或凋亡或各种基因表达的调节中发挥关键作用。尽管 MAPK 对体外细胞功能至关重要，但人们对 MAPK 在体内心血管系统病理生理学中的作用知之甚少。我们检查了 MAPK 在各种心血管疾病模型中的活性。在高血压大鼠或输注血管紧张素 II 的大鼠心脏肥大中，JNK 活性长期增强，随后激活蛋白 1 (AP-1) 活性增加。心脏 JNK 活性增加与心脏肥大的发展相关，表明 JNK 在心脏肥大中的作用。慢性高血压大鼠血管ERK和JNK活性较正常血压大鼠持续升高，并伴有血管增厚。此外，球囊损伤快速且短暂地激活血管 ERK 和 JNK，随后激活 AP-1。受损动脉中 ERK 和 JNK 的激活部分被 AT1 受体拮抗剂阻断，表明 AT1 受体在受损动脉中 ERK 和 JNK 激活中的贡献。 ERK 或 JNK 显性干扰突变体的体内基因转移可防止球囊损伤后血管新内膜的形成。因此，JNK 或 ERK 的激活增强发生在各种心血管疾病模型中，支持了 MAPK 可能对心血管肥大和重塑很重要的观点。