Yano M, Kim S, Izumi Y, Yamanaka S, Iwao H
Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.
Circ Res. 1998 Oct 5;83(7):752-60. doi: 10.1161/01.res.83.7.752.
Two subgroups of mitogen-activated protein kinases, c-jun NH2-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng . kg-1 . min-1) infusion caused larger activation of left ventricular JNK than ERK, via the AT1 receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT1 receptor. The dose-response relationships for Ang II-induced rises in blood pressure and cardiac JNK and ERK activation indicated that cardiac JNK or ERK was not activated by a mild increase in blood pressure and that cardiac JNK was activated by Ang II-mediated hypertension in a more sensitive manner than ERK. Cardiac hypertrophy, induced by chronic Ang II infusion, was preceded by JNK activation without ERK activation. Furthermore, gel mobility shift analysis showed that cardiac JNK activation was followed by increased activator protein-1 DNA binding activity due to c-Fos and c-Jun. These results provided the first evidence for the preferential activation of cardiac JNK in Ang II-induced hypertension and suggested that JNK might play some role in Ang II-induced cardiac hypertrophic response in vivo. However, further study is needed to elucidate the role of JNK in cardiac hypertrophy in vivo.
有丝分裂原活化蛋白激酶的两个亚组，即c-jun氨基末端激酶（JNK）和细胞外信号调节激酶（ERK），被认为参与了培养的心肌细胞肥大和基因表达过程。为了检测这些激酶在体内的激活情况，我们采用凝胶内激酶法，测量了急性或慢性输注血管紧张素II（Ang II）的清醒大鼠心脏中的JNK和ERK活性。通过AT1受体，输注Ang II（1000 ng·kg-1·min-1）使血压升高约50 mmHg，导致左心室JNK的激活程度大于ERK。尽管Ang II使血压达到最大值的持续时间较短（约30分钟），但JNK在15分钟至至少3小时内维持峰值（增加超过5倍）。右心室也出现了类似的JNK激活。因此，Ang II对心脏JNK的激活似乎部分是通过其经由AT1受体的直接作用介导的。Ang II诱导的血压升高与心脏JNK和ERK激活之间的剂量反应关系表明，轻度血压升高不会激活心脏JNK或ERK，并且Ang II介导的高血压以比ERK更敏感的方式激活心脏JNK。慢性输注Ang II诱导的心脏肥大之前，JNK被激活而ERK未被激活。此外，凝胶迁移率变动分析表明，心脏JNK激活后，由于c-Fos和c-Jun，激活蛋白-1的DNA结合活性增加。这些结果首次证明了在Ang II诱导的高血压中，心脏JNK被优先激活，并提示JNK可能在体内Ang II诱导的心脏肥大反应中发挥一定作用。然而，需要进一步研究来阐明JNK在体内心脏肥大中的作用。
