Fischer T A, Singh K, O'Hara D S, Kaye D M, Kelly R A
Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Am J Physiol. 1998 Sep;275(3):H906-16. doi: 10.1152/ajpheart.1998.275.3.H906.
ANG II has been implicated in the hypertrophic response in ventricular myocytes by acting at the angiotensin type 1 (AT1) receptor. However, the role of the angiotensin type 2 (AT2) receptor in the adult heart is not as clearly understood. In adult rat ventricular myocytes (ARVM) and cardiac microvascular endothelial cells (CMEC), we examined the role of ANG II signaling, via AT1 and AT2 receptors, on the activation of the extracellular signal-regulated protein kinases (ERKs) and on the expression of the mitogen-activated protein kinase (MAPK) phosphatase MKP-1. ANG II caused no detectable increase in ERK activity or in c-fos mRNA abundance in ARVM but increased ERK activity within 5 min in CMEC and increased c-fos mRNA levels. However, in the presence of the selective phosphoprotein phosphatase (PP-2A/PP-1) inhibitor okadaic acid (OA), a sustained increase in ERK activity, as well as in c-jun NH2-terminal protein kinase activity, in ARVM was observed. ANG II increased MKP-1 mRNA levels within 15 min in ARVM and CMEC. In contrast to the response in endothelial cells, however, ANG II activation of MKP-1 in ARVM was mediated by AT2-receptor activation. Thus there is constitutive as well as inducible suppression of ERKs and c-jun NH2-terminal protein kinases by MKP and PP-2A/PP-1 in the adult cardiac myocyte phenotype.
血管紧张素II（ANG II）通过作用于1型血管紧张素（AT1）受体，参与心室肌细胞的肥大反应。然而，2型血管紧张素（AT2）受体在成体心脏中的作用尚不清楚。在成年大鼠心室肌细胞（ARVM）和心脏微血管内皮细胞（CMEC）中，我们研究了ANG II通过AT1和AT2受体信号传导对细胞外信号调节蛋白激酶（ERK）激活以及丝裂原活化蛋白激酶（MAPK）磷酸酶MKP-1表达的作用。ANG II未引起ARVM中ERK活性或c-fos mRNA丰度的可检测增加，但在CMEC中5分钟内增加了ERK活性，并增加了c-fos mRNA水平。然而，在存在选择性磷蛋白磷酸酶（PP-2A/PP-1）抑制剂冈田酸（OA）的情况下，观察到ARVM中ERK活性以及c-jun NH2末端蛋白激酶活性持续增加。ANG II在ARVM和CMEC中15分钟内增加了MKP-1 mRNA水平。然而，与内皮细胞中的反应不同，ANG II在ARVM中对MKP-1的激活是由AT2受体激活介导的。因此，在成年心肌细胞表型中，MKP和PP-2A/PP-1对ERK和c-jun NH2末端蛋白激酶存在组成性和诱导性抑制作用。
