Transcription of early developmental isogenes in cardiac myocyte hypertrophy.
Transcription of early developmental isogenes in cardiac myocyte hypertrophy.
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DOI：
10.1016/0022-2828(89)90774-8
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发表时间：
1989-12
影响因子：
5
通讯作者：
P. C. Simpson;Carlin S. Long;L. Waspe;Curtis J. Henrich;C. Ordahl
中科院分区：
文献类型：
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作者：
P. C. Simpson;Carlin S. Long;L. Waspe;Curtis J. Henrich;C. Ordahl
我们建立了一个细胞培养系统来研究心肌肥大的重要分子机制。α1-肾上腺素能受体刺激引起新生大鼠心肌细胞肥大。尽管在其他类型的细胞中观察到α1肾上腺素能受体介导的DNA合成和细胞分裂，但α 1刺激不会诱导肌细胞增生。肌细胞肥大反应不需要收缩活动。α 1受体的激活也产生基因表达的高度特异性改变，如在mRNA和蛋白质水平上测量的。特别是，在早期发育和压力负荷肥大中，骨骼α-肌动蛋白和β-肌球蛋白重链在体内表达的两种收缩蛋白同源基因有选择性上调。体外转录实验表明，刺激α1-肾上腺素能受体可导致转录激活的独特时序。骨骼肌α-肌动蛋白同功基因的转录优先于心脏α-肌动蛋白的转录。因此，在α1刺激的肥大中，早期发育同基因诱导反映了心肌细胞核转录程序的根本变化。现在的目标是确定连接质膜中α1-肾上腺素能受体与心肌细胞核中骨骼α-肌动蛋白基因上RNA聚合酶II激活的细胞内途径。有证据表明，蛋白激酶C可能是这一途径的一个组成部分。提出了一个α1介导的转录模型。
We have developed a cell culture system to study molecular mechanisms important in myocardial hypertrophy.α1-Adrenergic receptor stimulation produces hypertrophy of neonatal rat cardiac myocytes. Myocyte hyperplasia is not induced byα1stimulation, althoughα1-adrenergic receptor-mediated DNA synthesis and cell division have been observed in other types of cells. The myocyte hypertrophic response does not require contractile activity. Activation of theα1receptor also produces highly specific alterations in gene expression, as measured at the mRNA and protein levels. In particular, there is selective up-regulation of two contractile protein isogenes that are expressedin vivoduring early development and in pressure-load hypertrophy, skeletal α-actin and β-myosin heavy chain. Studies with anin vitrotranscription assay indicate that stimulation of theα1-adrenergic receptor leads to a distinctive temporal sequence of transcriptional activation. Transcription of the skeletal α-actin isogene is induced preferentially to that of cardiac α-actin. Thus, early developmental isogene induction inα1-stimulated hypertrophy reflects a fundamental change in the transcriptional program of the cardiac myocyte nucleus. The goal now is to define an intracellular pathway connecting theα1-adrenergic receptor in the plasma membrane to activation of RNA polymerase II on the skeletal α-actin gene in the cardiac myocyte nucleus. There is evidence that protein kinase C may be one component of this pathway. A model forα1-mediated transcription is presented.