Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways
Phenylephrine induces activation of CREB in adult rat cardiac myocytes through MSK1 and PKA signaling pathways
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DOI：
10.1016/j.yjmcc.2004.08.002
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发表时间：
2004-11-01
影响因子：
5
通讯作者：
Lazou, A
中科院分区：
文献类型：
--
作者：
Markou, T;Hadzopoulou-Cladaras, M;Lazou, A
cAMP反应元件结合蛋白（CREB）是一种刺激诱导的转录因子，可能与心脏的病理生理有关。在本研究中，我们提供的证据表明，肥厚性激动剂苯肾上腺素（PE）通过α(1)-和β肾上腺素能受体促进成年大鼠心肌细胞中CREB的磷酸化。pe诱导的CREB磷酸化被Ro318220和1489部分抑制，Ro318220和1489被证明是丝裂原和应激激活蛋白激酶-1 （MSK1）激活的有效抑制剂，暗示该激酶参与了反应。当心肌细胞被ERK1/2和p38 MAPK通路抑制剂处理时，也获得了类似的结果。此外，RpcAMP对蛋白激酶A的抑制降低了CREB的磷酸化，表明该途径也参与其中。此外，PE刺激还伴随着CREB结合活性的增加，而阻止CREB磷酸化的药物会降低CREB结合活性。还观察到CBP/phospho-CREB复合物形成增强，表明CBP募集磷酸化CREB。这些结果表明，PE通过涉及ERK1/2的多种信号通路刺激成年大鼠心室肌细胞CREB的磷酸化和DNA结合活性。p38 MAPK， MSK1和PKA。同样的途径似乎调节心房利钠肽（ANF） mRNA的表达，这是一种高度保守的心脏肥厚标记基因，表明pe刺激的CREB激活可能在肥厚反应中发挥重要作用。(C) 2004 Elsevier Ltd.版权所有。
cAMP responsive element binding protein (CREB) is a stimulus induced transcription factor with possible relevance for the pathophysiology of the heart. In the present study, we provide evidence that the hypertrophic agonist, phenylephrine (PE), promotes phosphorylation of CREB in adult rat cardiac myocytes through alpha(1)- and beta-adrenergic receptors. PE-induced phosphorylation of CREB was partially inhibited by Ro318220 and 1489, which were shown to be potent inhibitors of mitogen- and stress-activated protein kinase-1 (MSK1) activation, implicating the involvement of this kinase in the response. Similar results were obtained when cardiac myocytes were treated with the inhibitors of ERK1/2 and p38 MAPK pathways. In addition, inhibition of protein kinase A by RpcAMP reduced phosphorylation of CREB, suggesting that this pathway is also involved. Furthermore, PE stimulation was accompanied by an increase in CRE-binding activity, which was reduced by drugs that prevented phosphorylation of CREB. An enhanced CBP/phospho-CREB complex formation was also observed, suggesting recruitment of CBP to phosphorylated CREB. These results suggest that PE stimulates phosphorylation and DNA binding activity of CREB in adult rat ventricular myocytes through multiple signaling pathways involving ERK1/2. p38 MAPK, MSK1 and PKA. The same pathways seem to regulate atrial natriuretic peptide (ANF) mRNA expression, a highly conserved marker gene of cardiac hypertrophy suggesting that the PE-stimulated activation of CREB is likely to play an important role in the hypertrophic response. (C) 2004 Elsevier Ltd. All rights reserved.