Mechanical strain activates BNP gene transcription through a p38/NF-κB-dependent mechanism
Mechanical strain activates BNP gene transcription through a p38/NF-κB-dependent mechanism
复制标题
DOI：
10.1172/jci7362
复制
发表时间：
1999-12-01
影响因子：
15.9
通讯作者：
Gardner, DG
中科院分区：
文献类型：
--
作者：
Liang, FQ;Gardner, DG
将机械菌株应用于培养的新生大鼠心室肌细胞，会引起基因表达的变化，让人想起体内肥大时发生的变化，例如刺激脑利钠肽（BNP）基因表达。在这里，我们发现菌株依赖的BNP启动子激活的一个主要成分是刺激心肌细胞中的p38丝裂原活化蛋白激酶（MAPK）。菌株以时间依赖性的方式增加p38活性。p38抑制剂SB203580导致菌株激活的人BNP （hbbnp）启动子活性降低约60%。共转染野生型p38增加了基础启动子和菌株依赖的启动子活性，而共转染MKK6AL （p38 MAPK激酶的显性阴性抑制剂）导致p38或菌株激活的hBNP启动子活性部分抑制。p38 MAPK通过激活转录因子NF-kappa b来增加hBNP启动子活性，p38或菌株激活hBNP启动子都是由基因5'侧序列中的DNA元件介导的。机械应变促进NF-kappa B组分在这些DNA元件上的体外组装。因此，机械应变对hBNP启动子的诱导至少部分取决于p38的刺激和随后NF-kappa b的激活，这种激活可能在体内伴随血流动力学超载和心脏肥大的BNP基因表达增加的信号传导中起重要作用。
Application of mechanical strain to neonatal rat ventricular myocytes in culture evokes changes in gene expression reminiscent of those that occur with hypertrophy in vivo, such as stimulation of brain natriuretic peptide (BNP) gene expression Here, we show that a major component of strain-dependent BNP promoter activation results from stimulation of p38 mitogen-activated protein kinase (MAPK) in the cardiac myocyte. Strain increased p38 activity in a time-dependent fashion. The p38 inhibitor SB203580 led to a reduction of approximately 60% in strain-activated human BNP (hBNP) promoter activity. Cotransfection of wild-type p38 increased both basal and strain-dependent promoter activity, while cotransfection with MKK6AL, a dominant-negative inhibitor of p38 MAPK kinase, resulted in partial inhibition of either p38- or strain-activated hBNP promoter activity. p38 MAPK increased hBNP promoter activity through activation of the transcription factor NF-kappa B. Activation of the hBNP promoter by either p38 or strain was mediated by DNA elements present in the 5' flanking sequence of the gene. Mechanical strain promoted assembly of NF-kappa B components on these DNA elements in vitro. Thus, induction of the hBNP promoter by mechanical strain depends, at least in part, on stimulation of p38 and subsequent activation of NF-kappa B. This activation may play an important role in signaling the increased BNP gene expression that accompanies hemodynamic overload and cardiac hypertrophy in vivo.