Calcineurin enhances MAPK phosphatase-1 expression and p38 MAPK inactivation in cardiac myocytes
Calcineurin enhances MAPK phosphatase-1 expression and p38 MAPK inactivation in cardiac myocytes
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DOI：
10.1074/jbc.m100452200
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发表时间：
2001-05-11
影响因子：
4.8
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Lim, HW;New, L;Molkentin, JD
多种细胞内信号通路调节心肌细胞的肥厚生长，包括丝裂原活化蛋白激酶（MAPK）和活化t细胞的钙调磷酸酶核因子。然而，尚不确定单个调控通路是独立运作的，还是不相关通路之间的相互连接是整个肥厚反应协调所必需的。为此，我们在体外和体内研究了钙调磷酸酶介导的心肌细胞肥大与p38 MAPK信号传导之间的相互联系。研究表明，钙调磷酸酶可下调p38 MAPK活性，并增强双特异性磷酸酶MAPK磷酸酶-1 （MKP-1）的表达。在心脏中表达活化钙调磷酸酶的转基因小鼠，在出生后早期发育过程中，在心肌肥厚发生之前，p38失活，MKP-1表达增加。在体外，用表达钙调磷酸酶的腺病毒感染培养的新生儿心肌细胞，并用苯肾上腺素刺激，显示p38磷酸化降低，MKP-1蛋白水平升高。钙离子载体A23187激活内源性钙调神经磷酸酶可降低p38磷酸化，增加MKP-1蛋白水平。环孢素A抑制内源性钙调磷酸酶降低MKP-1蛋白水平，增加激动剂刺激下p38的激活。为了进一步通过改变MKP-1的表达来研究钙调神经磷酸酶和p38之间潜在的相互作用，我们对MKP-1启动子进行了表征，并确定其对钙调神经磷酸酶有反应。这些数据表明，钙调磷酸酶增强心肌细胞中MKP-1的表达，这与p38失活有关。
Multiple intracellular signaling pathways have been shown to regulate the hypertrophic growth of cardiac myocytes including mitogen-activated protein kinase (MAPK) and calcineurin-nuclear factor of activated T-cells. However, it is uncertain if individual regulatory pathways operate in isolation or if interconnectivity between unrelated pathways is required for the orchestration of the entire hypertrophic response. To this end, we investigated the interconnectivity between calcineurin-mediated cardiac myocyte hypertrophy and p38 MAPK signaling in vitro and in vivo. We show that calcineurin promotes down-regulation of p38 MAPK activity and enhances expression of the dual specificity phosphatase MAPK phosphatase-1 (MKP-1). Transgenic mice expressing activated calcineurin in the heart were characterized by inactivation of p38 and increased MKP-1 expression during early postnatal development, before the onset of cardiac hypertrophy, In vitro, cultured neonatal cardiomyocytes infected with a calcineurin-expressing adenovirus and stimulated with phenylephrine demonstrated reduced p38 phosphorylation and increased MKP-1 protein levels. Activation of endogenous calcineurin with the calcium ionophore A23187 decreased p38 phosphorylation and increased MKP-1 protein levels. Inhibition of endogenous calcineurin with cyclosporin A decreased MKP-1 protein levels and increased p38 activation in response to agonist stimulation. To further investigate potential cross-talk between calcineurin and p38 through alteration in MKP-1 expression, the MKP-1 promoter was characterized and determined to be calcineurin-responsive. These data suggest that calcineurin enhances MKP-1 expression in cardiac myocytes, which is associated with p38 inactivation.