An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities.
An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities.
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DOI：
10.3390/ijms18061268
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发表时间：
2017-06-14
影响因子：
5.6
通讯作者：
Tamura K
中科院分区：
文献类型：
--
作者：
Minegishi S;Ishigami T;Kawamura H;Kino T;Chen L;Nakashima-Sasaki R;Doi H;Azushima K;Wakui H;Chiba Y;Tamura K
我们以前已经表明，神经前体细胞表达的发育下调基因4-2（Nedd 4 -2）亚型与C2结构域密切相关的上皮钠通道（ENaC）的泛素化，导致盐敏感性高血压的Nedd 4 -2 C2靶向小鼠。钠电压门控通道α亚基5（SCN 5A）基因编码人心脏电压门控钠通道（I Na）的α亚基，钾电压门控通道亚家族H成员2（KCNH 2）基因编码快速激活延迟整流钾通道（I Kr）。这两种离子通道也已被证明通过C-末端的保守脯氨酸-酪氨酸（PY）基序结合Nedd 4 -2，随后被蛋白酶体泛素化和降解。因此，Nedd 4 - 2C 2亚型的丢失可能参与各种条件下的电生理损伤。我们在这里证明，Nedd 4 -2 C2亚型引起心脏传导的变化，在静息状态下，以及急性心肌梗死（MI）后的预防性变化。Nedd 4 -2 C2基因敲除（KO）小鼠在静息状态下表现出心动过缓、QRS、QT间期延长和PR间期抑制。此外，在手术结扎左冠状动脉远端的小鼠中发现T峰/T末间期增强。基于活体心脏超声检查以及组织病理学结果的形态学分析显示，Nedd 4 -2 C2 KO小鼠在静息条件下与野生型同窝小鼠相比未显示出显著的结构变化。这些结果表明，Nedd 4 -2与C2结构域可能通过转录后修饰ENaC和心脏离子通道，这是肾脏和心脏功能的关键，在心肾综合征中发挥重要作用。
We have previously shown that neural precursor cell-expressed developmentally downregulated gene 4-2 (Nedd4-2) isoforms with a C2 domain are closely related to ubiquitination of epithelial sodium channel (ENaC), resulting in salt-sensitive hypertension by Nedd4-2 C2 targeting in mice. The sodium voltage-gated channel alpha subunit 5 (SCN5A) gene encodes the α subunit of the human cardiac voltage-gated sodium channel (I Na), and the potassium voltage-gated channel subfamily H member 2 (KCNH2) gene encodes rapidly activating delayed rectifier K channels (I Kr). Both ion channels have also been shown to bind to Nedd4-2 via a conserved Proline-Tyrosine (PY) motif in C-terminal with subsequent ubiquitination and degradation by proteasome. Therefore, loss of Nedd4-2 C2 isoform might be involved in electrophysiological impairment under various conditions. We demonstrate here that Nedd4-2 C2 isoform causes cardiac conduction change in resting condition as well as proarrhythmic change after acute myocardial infarction (MI). The Nedd4-2 C2 knockout (KO) mice showed bradycardia, prolonged QRS, QT intervals, and suppressed PR interval in resting condition. In addition, enhancement of T peak/T end interval was found in mice with surgical ligation of the distal left coronary artery. Morphological analyses based on both ultrasonography of the living heart, as well as histopathological findings revealed that Nedd4-2 C2 KO mice show no significant structural changes from wild-type littermates under resting conditions. These results suggested that Nedd4-2 with C2 domain might play an important role in cardio-renal syndrome through post-transcriptional modification of both ENaC and cardiac ion channels, which are critical for kidney and heart functions.