Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability
Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability
复制标题
DOI：
10.1161/01.res.0000215985.18538.c4
复制
发表时间：
2006-03-31
影响因子：
20.1
通讯作者：
Molkentin, JD
中科院分区：
文献类型：
--
作者：
Oka, T;Maillet, M;Molkentin, JD
转录因子GATA4是心脏基因表达的关键调节因子，在那里它控制着胚胎发育、心肌细胞分化和成人心脏的应激反应。传统的GATA4缺失导致胚胎死亡与内胚层缺陷和心脏畸形相关，排除了对GATA4在成人心肌中的作用的分析。为了研究GATA4在成人心脏中的功能，以GATA4-loxP为靶标的小鼠(Gata4fl/f1)与含有β-肌球蛋白重链(beta-MHC)或α-MHC启动子驱动的Cre转基因的小鼠杂交，这些转基因小鼠产生了存活的小鼠，尽管GATA4蛋白分别丢失了95%和70%，但仍能存活到成年。然而，心脏特异的Gata4缺失导致成年后心功能和扩张的进行性和剂量依赖性的恶化。此外，压力超负荷刺激导致心脏特异的Gata4基因缺失小鼠迅速失代偿和心力衰竭。更具挑衅性的是，GATA4基因缺失的小鼠在压力超负荷或运动刺激后肥大的能力受到损害。从机制上讲，心脏特异的Gata4缺失增加了胚胎和成年心肌细胞在基线时的TUNEL，以及在压力超负荷刺激后显著增加的TUNEL。对心脏基因表达谱的研究发现，已知的GATA4调控的结构基因以及与细胞凋亡有关的基因发生了一些深刻的变化。因此，GATA4是心脏基因表达、肥大、应激补偿和心肌细胞活性的必要调节因子。
The transcription factor GATA4 is a critical regulator of cardiac gene expression where it controls embryonic development, cardiomyocyte differentiation, and stress responsiveness of the adult heart. Traditional deletion of Gata4 caused embryonic lethality associated with endoderm defects and cardiac malformations, precluding an analysis of the role of GATA4 in the adult myocardium. To address the function of GATA4 in the adult heart, Gata4-loxP-targeted mice (Gata4fl/fl) were crossed with mice containing a beta-myosin heavy chain (beta-MHC) or alpha-MHC promoter-driven Cre transgene, which produced viable mice that survived into adulthood despite a 95% and 70% loss of GATA4 protein, respectively. However, cardiac-specific deletion of Gata4 resulted in a progressive and dosage-dependent deterioration in cardiac function and dilation in adulthood. Moreover, pressure overload stimulation induced rapid decompensation and heart failure in cardiac-specific Gata4-deleted mice. More provocatively, Gata4-deleted mice were compromised in their ability to hypertrophy following pressure overload or exercise stimulation. Mechanistically, cardiac-specific deletion of Gata4 increased cardiomyocyte TUNEL at baseline in embryos and adults as they aged, as well as dramatically increased TUNEL following pressure overload stimulation. Examination of gene expression profiles in the heart revealed a number of profound alterations in known GATA4-regulated structural genes as well as genes with apoptotic implications. Thus, GATA4 is a necessary regulator of cardiac gene expression, hypertrophy, stress-compensation, and myocyte viability.