Transcriptional upregulation of calcineurin Aβ by endothelin-1 is partially mediated by calcium/calmodulin-dependent protein kinase IIδ3 in rat cardiomyocytes
Transcriptional upregulation of calcineurin Aβ by endothelin-1 is partially mediated by calcium/calmodulin-dependent protein kinase IIδ3 in rat cardiomyocytes
复制标题
DOI：
10.1016/j.bbagrm.2010.02.004
复制
发表时间：
2010-05-01
影响因子：
4.7
通讯作者：
Fukunaga, Kohji
中科院分区：
文献类型：
--
作者：
Lu, Ying-Mei;Shioda, Norifumi;Fukunaga, Kohji
钙/钙调素依赖的蛋白激酶II(CaMKII)和钙调神经磷酸酶(CaN)是心肌肥厚的正性调节因子，但CaMKII和CaN信号通路在肥厚心肌细胞中的相互作用性质尚不清楚。在此，我们证明CaMKII delta3的激活通过激活CaN-Aβ亚基(CNAβ)启动子来增强培养的大鼠心肌细胞CaN基因的转录。免疫共沉淀分析表明，将活性CaMKII delta3(T278D)突变体导入新生心肌细胞后，MEF2与GATA4形成复合体。相反，转染显性负CaMKII Delta 3突变体未能促进MEF2-GATA4复合体的形成。与这些观察结果一致，免疫细胞化学显示肥大激动剂刺激或CaMKII Delta 3(T278D)转染后MEF2与GATA4的核共存。这些数据表明，CaMKII可以通过增强MEF2-GATA4的协同作用来增强CNAβ启动子的活性，这可能是CaMKII介导的肥大信号的一种新的机制，有助于通过激活CaN来诱导和发展肥大反应。(C)2010爱思唯尔B.V.保留所有权利。
Ca2+/calmodulin-dependent protein kinase II (CaMKII) and calcineurin (CaN) are positive regulators of cardiac hypertrophy, but the nature of cross-talk between CaMKII and CaN signaling pathways in hypertrophic cardiomyocytes remains unclear. Here we documented that CaMKII delta 3 activation enhances transcription of the CaN gene through activation of the CaN-A beta subunit (CnA beta) promoter in rat cultured cardiomyocytes. Co-immunoprecipitation assays showed that MEF2 forms a complex with GATA4 following transfection of an active CaMKII delta 3 (T278D) mutant in neonatal cardiomyocytes. Inversely, transfection of a dominant negative CaMKII delta 3 mutant failed to promote a MEF2-GATA4 complex. Consistent with these observations, immunocytochemistry indicated nuclear co-localization of MEF2 with GATA4 after hypertrophic agonist stimulation or CaMKII delta 3 (T278D) transfection. These data demonstrate that CaMKII can enhance CnA beta promoter activity by enhancing MEF2-GATA4 synergy, suggesting a novel mechanism for CaMKII-mediated hypertrophic signaling, which contributes to induction and development of the hypertrophic response through CaN activation. (C) 2010 Elsevier B.V. All rights reserved.