Izumi Y, Kim S, Zhan Y, Namba M, Yasumoto H, Iwao H
Department of Pharmacology, Osaka City University Medical School, Osaka 545-8585, Japan.
Hypertension. 2000 Oct;36(4):511-6. doi: 10.1161/01.hyp.36.4.511.
In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH(2)-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT(1)) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT(1) receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT(1) receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT(1) receptor-mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
关于丝裂原活化蛋白（MAP）激酶家族（细胞外信号调节激酶[ERK]、c-Jun氨基末端激酶[JNK]和p38）在心脏肥厚反应中的作用的体外研究产生了令人困惑和矛盾的结果。我们研究了1型血管紧张素II（AT(1)）受体在易中风自发性高血压大鼠（SHRSP）心脏肥厚发生和发展过程中对心脏MAP激酶活性的体内作用。在SHRSP心脏肥厚的急性和慢性阶段，与正常血压大鼠相比，心脏JNK活性显著增加，而SHRSP心脏ERK或p38活性没有明显增加。AT(1)受体拮抗剂氯沙坦可预防SHRSP心脏肥厚的发生并使心脏肥厚进展消退，同时伴随着SHRSP中JNK活性和激活蛋白-1（AP-1）活性的降低。然而，尽管血压恢复正常，肼屈嗪并不能预防或消退SHRSP的心脏肥厚，也不能降低其JNK或AP-1活性。相反，肼屈嗪通过增强磷酸化作用显著增加了SHRSP的心脏ERK活性。总之，我们首次获得证据表明，AT(1)受体参与了高血压大鼠心脏肥厚发生和发展过程中心脏JNK活性的增强。我们提出，JNK参与了体内AT(1)受体介导的心脏肥厚，部分是由AP-1的激活介导的。
