The role of p38 in the regulation of Na+-Ca2+ exchanger expression in adult cardiomyocytes.
The role of p38 in the regulation of Na+-Ca2+ exchanger expression in adult cardiomyocytes.
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p38 在调节成人心肌细胞 Na -Ca2 交换器表达中的作用。
DOI：
10.1016/j.yjmcc.2005.03.002
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发表时间：
2005
影响因子：
5
通讯作者：
Menick,DonaldR
中科院分区：
文献类型：
--
作者：
Xu,Lin;Kappler,ChristianaS;Menick,DonaldR
Na+ -Ca2 +交换器在心肌细胞[Ca2+]调控中起着至关重要的作用。在心脏肥厚和衰竭时，交换器被上调。这种上调可对钙瞬变产生影响，并可能导致舒张功能障碍和心律失常的风险增加。在这里，我们使用腺病毒介导的基因表达来检测p38 MAP激酶在成人心肌细胞交换蛋白上调中的作用。我们证明p38介导部分α-肾上腺素能刺激的Na+ -Ca2 +交换基因上调。在分离的成人心肌细胞中，显性阴性p38亚型的过表达和活化的MKK3和MKK6表明p38激活足以导致NCX1启动子上调，并且这主要是由p38α亚型介导的。最后，本研究表明p38α刺激的NCX1启动子上调是通过-80 CArG盒元件介导的。这是第一次在分离的成人心肌细胞中证实p38α在基因调控中的特定作用，并为我们理解肥厚和衰竭心脏中调节交换基因表达的一些因素提供了重要线索。
The Na+–Ca2+exchanger is crucial in the regulation of [Ca2+]iin the cardiac myocyte. The exchanger is upregulated in cardiac hypertrophy and failure. This upregulation can have an effect on calcium transients and possibly contribute to diastolic dysfunction and an increased risk of arrhythmias. Here we use adenovirus mediated gene expression to examine the role of p38 MAP kinase in upregulation of the exchanger in adult cardiac myocytes. We demonstrate that p38 mediates a part of the α-adrenergic stimulated upregulation of the Na+–Ca2+exchanger gene. Overexpression of dominant-negative p38 isoforms and activated MKK3 and MKK6 in isolated adult cardiac myocytes demonstrates that p38 activation is sufficient for NCX1 promoter upregulation and that this is mediated primarily by the p38α isoform. Lastly, this work demonstrates that the p38α stimulated upregulation of the NCX1 promoter is mediated via the –80 CArG box element. This is the first time that a specific role for p38α in gene regulation has been demonstrated in isolated adult cardiomyocytes and provides an important clue to our understanding some of the factors regulating exchanger gene expression in the hypertrophic and failing heart.