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

细胞外信号调节激酶（ERK）和c-jun氨基末端激酶（JNK）属于丝裂原活化蛋白激酶（MAPK），在调节细胞生长、凋亡及多种基因表达等方面发挥重要作用。尽管MAPK在体外对细胞功能至关重要，但MAPK在体内心血管系统病理生理学中的作用知之甚少。我们研究了MAPK在各种心血管疾病模型中的活性。JNK活性在高血压大鼠或血管紧张素II灌注大鼠的心脏肥大中慢性增强，随后是激活蛋白-1（AP-1）活性的增加。心肌JNK活性升高与心肌肥厚的发生发展有关，提示JNK在心肌肥厚中的作用。在慢性高血压大鼠中，与正常血压大鼠相比，血管ERK和JNK活性持续增加，血管增厚。此外，球囊损伤迅速和短暂激活血管ERK和JNK，随后激活AP-1。AT 1受体拮抗剂可部分阻断ERK和JNK的激活，提示AT 1受体参与了ERK和JNK的激活。ERK或JNK显性干扰突变体的体内基因转移预防球囊损伤后血管新生内膜形成。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MAPK可能对心血管肥大和重塑很重要的观点。

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.