Transcription Factor GATA4 Is Activated but Not Required for Insulin-like Growth Factor 1 (IGF1)-induced Cardiac Hypertrophy
Transcription Factor GATA4 Is Activated but Not Required for Insulin-like Growth Factor 1 (IGF1)-induced Cardiac Hypertrophy
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DOI：
10.1074/jbc.m111.338749
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发表时间：
2012-03-23
影响因子：
4.8
通讯作者：
Pieske, Burkert
中科院分区：
文献类型：
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作者：
Bisping, Egbert;Ikeda, Sadakatsu;Pieske, Burkert
胰岛素样生长因子1（IGF 1）促进一种生理类型的心脏肥大，并对心脏病有治疗作用。在这里，我们报告了IGF 1与GATA 4的关系，GATA 4是心脏肥大和细胞存活中的一个重要转录因子。在培养的新生大鼠心室肌细胞中，我们比较了IGF 1（10 nmol/L）和苯丙氨酸（PE，20 μ mol/L），一种已知的GATA 4激活剂，在浓度促进类似程度的肥大的反应。IGF 1和PE均增加了GATA 4的核积累和Ser（105）处的磷酸化（PE，2.4倍; IGF 1，1.8倍;两者，p < 0.05），并增加了GATA 4 DNA结合活性，如ELISA和所选启动子的染色质IP所示。虽然IGF 1和PE各自以相同的程度激活GATA 4，但通过RNA干扰敲低GATA 4仅阻断PE引起的肥大，而不阻断IGF 1。一组GATA 4靶基因（Nppa、Nppb、Tnni 3、Myl 1和Acta 1）的PE诱导被GATA 4敲低抑制。相反，IGF 1仅以GATA 4依赖的方式调节Acta 1。与体外研究结果一致，小鼠Gata 4单倍不足并没有改变心脏结构、高动力功能或由IGF 1受体心肌过表达诱导的抗纤维化作用。我们的数据表明，GATA 4是由IGF 1通路激活，但尽管它是对病理刺激的反应所必需的，但它不是IGF 1对心脏结构和功能的影响所必需的。
Insulin-like growth factor 1 (IGF1) promotes a physiological type of cardiac hypertrophy and has therapeutic effects in heart disease. Here, we report the relationship of IGF1 to GATA4, an essential transcription factor in cardiac hypertrophy and cell survival. In cultured neonatal rat ventricular myocytes, we compared the responses to IGF1 (10 nmol/liter) and phenylephrine (PE, 20 mu mol/liter), a known GATA4 activator, in concentrations promoting a similar extent of hypertrophy. IGF1 and PE both increased nuclear accumulation of GATA4 and phosphorylation at Ser(105) (PE, 2.4fold; IGF1, 1.8fold; both, p < 0.05) and increased GATA4 DNA binding activity as indicated by ELISA and by chromatin IP of selected promoters. Although IGF1 and PE each activated GATA4 to the same degree, GATA4 knockdown by RNA interference only blocked hypertrophy by PE but not by IGF1. PE induction of a panel of GATA4 target genes (Nppa, Nppb, Tnni3, Myl1, and Acta1) was inhibited by GATA4 knockdown. In contrast, IGF1 regulated only Acta1 in a GATA4-dependent fashion. Consistent with the in vitro findings, Gata4 haploinsufficiency in mice did not alter cardiac structure, hyperdynamic function, or antifibrotic effects induced by myocardial overexpression of the IGF1 receptor. Our data indicate that GATA4 is activated by the IGF1 pathway, but although it is required for responses to pathological stimuli, it is not necessary for the effects of IGF1 on cardiac structure and function.