Department of Cardiology, Medical University Graz, Auenbruggerplatz 15, 8036 Graz, Austria,; Department of Cardiology and Pneumology, Georg August University, Robert Koch Str. 40, 37075 Göttingen, Germany.
Department of Cardiology, Children's Hospital Boston, Boston, Massachusetts 02115.
J Biol Chem. 2012 Mar 23;287(13):9827-9834. doi: 10.1074/jbc.M111.338749. Epub 2012 Jan 6.
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 μmol/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, 2.4-fold; IGF1, 1.8-fold; 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.
胰岛素样生长因子 1（IGF1）促进生理性心肌肥厚，并在心 脏病中具有治疗作用。在这里，我们报告 IGF1 与 GATA4 之间 的关系，GATA4 是心肌肥厚和细胞存活的重要转录因子。在培 养的新生大鼠心室肌细胞中，我们比较了 IGF1（10nmol/L）和苯 肾上腺素（PE，20μmol/L）的反应，PE 和 IGF1 的浓度均能促进相 似程度的心肌肥厚。IGF1 和 PE 均增加了 GATA4 的核积累和丝氨 酸 105 位的磷酸化（PE，2.4 倍；IGF1，1.8 倍；均 p<0.05），并增 加了 GATA4 的 DNA 结合活性，如 ELISA 和选择启动子的染色质 IP 所示。尽管 IGF1 和 PE 均以相同的程度激活 GATA4，但 RNA 干扰的 GATA4 敲低仅阻断了 PE 但未阻断 IGF1 引起的心肌肥厚。PE 诱导的一组 GATA4 靶基因（Nppa、Nppb、Tnni3、Myl1 和 Acta1）的表达被 GATA4 敲低所抑制。相比之下，IGF1 仅以 GATA4 依赖的方式调节 Acta1。与体外研究结果一致，在 IGF1 受体过表达诱导的心肌中，小鼠 Gata4 半合子不足并未改变心脏结构、超动力功能或抗纤维化效 应。我们的数据表明，GATA4 被 IGF1 途径激活，尽管它是对病 理刺激的反应所必需的，但它不是 IGF1 对心脏结构和功能的作 用所必需的。
