PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis
PITX2 Insufficiency Leads to Atrial Electrical and Structural Remodeling Linked to Arrhythmogenesis
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DOI：
10.1161/circgenetics.110.958116
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发表时间：
2011-06-01
影响因子：
--
通讯作者：
Franco, Diego
中科院分区：
文献类型：
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作者：
Chinchilla, Ana;Daimi, Houria;Franco, Diego
背景-Pitx 2是一种同源异型盒转录因子，在胚胎发育早期左右决定中起关键作用。Pitx 2功能丧失的小鼠突变体显示早期胚胎致死性和严重的心脏畸形，证明了Pitx 2在心脏发生过程中的重要性。最近，独立的全基因组关联研究为PITX 2在成人心脏中的假定作用提供了新的证据。这些研究已经独立地报告了几个风险变种接近PITX 2基因座的染色体4 q25是强烈相关的房颤human.Methods和结果，我们首次表明，PITX 2C表达显着降低人类患者持续性房颤，从而提供了一个分子之间的联系PITX 2功能丧失和房颤。此外，室特异性Pitx 2条件性小鼠突变体的形态学、分子学和电生理学表征揭示，心房而非心室室特异性Pitx 2缺失导致成人心脏中动作电位振幅和静息膜电位的差异以及房室传导阻滞的ECG特征。心房肌Pitx 2的缺乏损害钠通道和钾通道的表达，部分介导的miRNA misexpressions. Conclusions-本研究因此确定Pitx 2作为心房电功能的上游转录调节因子，其不足导致细胞和分子的变化，导致心房电和结构重塑与mammogenesis。(Circ Genet. 2011; 4：269-279）。
Background-Pitx2 is a homeobox transcription factor that plays a pivotal role in early left/right determination during embryonic development. Pitx2 loss-of-function mouse mutants display early embryonic lethality with severe cardiac malformations, demonstrating the importance of Pitx2 during cardiogenesis. Recently, independent genome-wide association studies have provided new evidence for a putative role of PITX2 in the adult heart. These studies have independently reported several risk variants close to the PITX2 locus on chromosome 4q25 that are strongly associated with atrial fibrillation in humans.Methods and Results-We show for the first time that PITX2C expression is significantly decreased in human patients with sustained atrial fibrillation, thus providing a molecular link between PITX2 loss of function and atrial fibrillation. In addition, morphological, molecular, and electrophysiological characterization of chamber-specific Pitx2 conditional mouse mutants reveals that atrial but not ventricular chamber-specific deletion of Pitx2 results in differences in the action potential amplitude and resting membrane potential in the adult heart as well as ECG characteristics of atrioventricular block. Lack of Pitx2 in atrial myocardium impairs sodium channel and potassium channel expression, mediated in part by miRNA misexpression.Conclusions-This study thus identifies Pitx2 as an upstream transcriptional regulator of atrial electric function, the insufficiency of which results in cellular and molecular changes leading to atrial electric and structural remodeling linked to arrhythmogenesis. (Circ Cardiovasc Genet. 2011; 4: 269-279.)