The homeodomain transcription factor lrx5 establishes the mouse cardiac ventricular repolarization gradient
The homeodomain transcription factor lrx5 establishes the mouse cardiac ventricular repolarization gradient
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DOI：
10.1016/j.cell.2005.08.004
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发表时间：
2005-10-21
期刊：
影响因子：
64.5
通讯作者：
Bruneau, BG
中科院分区：
文献类型：
--
作者：
Costantini, DL;Arruda, EP;Bruneau, BG
有节律的心脏收缩取决于去极化和复极化波前的有组织传播。复极化在空间上是异质的，很大程度上取决于钾电流的梯度。心脏病的梯度破坏可能是致命性心律失常的易感性的基础，但目前尚不清楚这种梯度是如何建立的。我们发现，在缺乏同源域转录因子 Irx5 的小鼠中，由于心内膜心肌中 K(v)4.2 钾通道表达增加，心脏复极梯度被消除，导致主要心脏复极电流 I-to、I-f 选择性增加，并增加心律失常的易感性。心肌 Irx5 以与 K(v)4.2 相反的梯度表达，并且 Irx5 通过募集 mBop（一种心脏转录抑制因子）来抑制 K(v)4.2 表达。因此，Irx5 阻遏物梯度负向调节心脏中钾通道基因的表达，形成逆 I-to,I-f 梯度，确保协调心脏复极，同时防止心律失常。
Rhythmic cardiac contractions depend on the organized propagation of depolarizing and repolarizing wavefronts. Repolarization is spatially heterogeneous and depends largely on gradients of potassium currents. Gradient disruption in heart disease may underlie susceptibility to fatal arrhythmias, but it is not known how this gradient is established. We show that, in mice lacking the homeodomain transcription factor Irx5, the cardiac repolarization gradient is abolished due to increased K(v)4.2 potassium-channel expression in endocardial myocardium, resulting in a selective increase of the major cardiac repolarization current, I-to,I-f, and increased susceptibility to arrhythmias. Myocardial Irx5 is expressed in a gradient opposite that of K(v)4.2, and Irx5 represses K(v)4.2 expression by recruiting mBop, a cardiac transcriptional repressor. Thus, an Irx5 repressor gradient negatively regulates potassium-channel-gene expression in the heart, forming an inverse I-to,I-f gradient that ensures coordinated cardiac repolarization while also preventing arrhythmias.