The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo
The transcription factors GATA4 and GATA6 regulate cardiomyocyte hypertrophy in vitro and in vivo
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DOI：
10.1074/jbc.m102174200
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发表时间：
2001-08-10
影响因子：
4.8
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Liang, QR;De Windt, LJ;Molkentin, JD
含锌指转录因子GATA4和GATA6是心肌和平滑肌细胞基础和诱导型基因表达的重要调节因子。在这里，我们展示了GATA4和GATA6作为心肌细胞肥大生长和基因表达调节因子的直接功能作用。为了模拟肥大刺激后内源性GATA4和GATA6转录活性的增加，利用重组腺病毒在心肌细胞中过表达了这两种因子。GATA4或GATA6的过表达足以诱导心肌细胞肥大，其特征是肌节组织增强，细胞表面积增加2倍以上，总蛋白积累显著增加。在体内，GATA4在成年心脏内过表达2.5倍的转基因小鼠在心脏/体重比、心肌病的组织学特征以及肥大相关基因的激活方面表现出缓慢的进展，表明GATA因子在体外和体内都足以调节心肌细胞的肥大。为了评估GATA因子作为肥大下游转录介质的需求，构建了显性负性GATA4抑制因子融合编码腺病毒。GATA4的表达阻断了GATA4和GATA6诱导的转录反应和激动剂诱导的心肌细胞肥大，表明心脏表达的GATA因子是这一过程中必要的中介。
The zinc finger-containing transcription factors GATA4 and GATA6 are important regulators of basal and inducible gene expression in cardiac and smooth muscle cell types. Here we demonstrate a direct functional role for GATA4 and GATA6 as regulators of cardiomyocyte hypertrophic growth and gene expression. To model the increase in endogenous GATA4 and GATA6 transcriptional activity that occurs in response to hypertrophic stimulation, each factor was overexpressed in cardiomyocytes using recombinant adenovirus. Overexpression of either GATA4 or GATA6 was sufficient to induce cardiomyocyte hypertrophy characterized by enhanced sarcomeric organization, a greater than 2-fold increase in cell surface area, and a significant increase in total protein accumulation. In vivo, transgenic mice with 2.5-fold overexpression of GATA4 within the adult heart demonstrated a slowly progressing increase in heart to body weight ratio, histological features of cardiomyopathy, and activation of hypertrophy-associated genes, suggesting that GATA factors are sufficient regulators of cardiomyocyte hypertrophy in vitro and in vivo. To evaluate the requirement of GATA factors as downstream transcriptional mediators of hypertrophy, a dominant negative GATA4-engrailed repressor fusion-encoding adenovirus was generated. Expression of GATA4-engrailed blocked GATA4- and GATA6-directed transcriptional responses and agonist-induced cardiomyocyte hypertrophy, demonstrating that cardiac-expressed GATA factors are necessary mediators of this process.