14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle
14-3-3ε Plays a Role in Cardiac Ventricular Compaction by Regulating the Cardiomyocyte Cell Cycle
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DOI：
10.1128/mcb.00829-12
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发表时间：
2012-12-01
影响因子：
5.3
通讯作者：
Brunelli, Luca
中科院分区：
文献类型：
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作者：
Kosaka, Yasuhiro;Cieslik, Katarzyna A.;Brunelli, Luca
在心脏发生早期，小梁心肌占心室的大部分，但致密心肌是发育后期的主要组成部分。阐明调节致密心肌发育的基因对于增加我们对左心室致密化不全（LVNC）的理解至关重要，左心室致密化不全是一种以小梁与致密心肌比例增加为特征的心肌病。 14-3-3 epsilon 是在侧板中胚层中表达的衔接蛋白，但其体内心脏功能仍有待确定。在这里，我们表明 14-3-3 epsilon 在发育中的小鼠心脏以及心肌细胞中表达。 14-3-3 epsilon 缺失似乎不会诱导其他 14-3-3 同工型的代偿，但会导致心室致密化不全，其特征与 LVNC 相似，这是由于致密心肌厚度的选择性减少所致。由于细胞周期 G(2)/M 期心肌细胞数量减少以及细胞周期 G(0)/G(1) 期心肌细胞积累，导致心脏增殖减少 50%，导致异常压实。这些缺陷源于细胞周期蛋白 E1 的下调和 p27(Kip1) 的上调，可能通过转录和翻译后机制。我们的工作表明，14-3-3 epsilon 通过细胞周期蛋白 E1 和 p27(Kip1) 调节心肌细胞周期来调节致密心室心肌的心脏发生和生长。这些数据与长期以来的观点一致，即人类 LVNC 可能是由致密性停滞引起的，并且它们暗示 14-3-3 epsilon 是先天性人类心肌病的新候选基因。
Trabecular myocardium accounts for the majority of the ventricles during early cardiogenesis, but compact myocardium is the primary component at later developmental stages. Elucidation of the genes regulating compact myocardium development is essential to increase our understanding of left ventricular noncompaction (LVNC), a cardiomyopathy characterized by increased ratios of trabecular to compact myocardium. 14-3-3 epsilon is an adapter protein expressed in the lateral plate mesoderm, but its in vivo cardiac functions remain to be defined. Here we show that 14-3-3 epsilon is expressed in the developing mouse heart as well as in cardiomyocytes. 14-3-3 epsilon deletion did not appear to induce compensation by other 14-3-3 isoforms but led to ventricular noncompaction, with features similar to LVNC, resulting from a selective reduction in compact myocardium thickness. Abnormal compaction derived from a 50% decrease in cardiac proliferation as a result of a reduced number of cardiomyocytes in G(2)/M and the accumulation of cardiomyocytes in the G(0)/G(1) phase of the cell cycle. These defects originated from downregulation of cyclin E1 and upregulation of p27(Kip1), possibly through both transcriptional and posttranslational mechanisms. Our work shows that 14-3-3 epsilon regulates cardiogenesis and growth of the compact ventricular myocardium by modulating the cardiomyocyte cell cycle via both cyclin E1 and p27(Kip1). These data are consistent with the long-held view that human LVNC may result from compaction arrest, and they implicate 14-3-3 epsilon as a new candidate gene in congenital human cardiomyopathies.