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Int. J. Mol. Sci. 2017, 18(6), 1268; doi:10.3390/ijms18061268

An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities

1
Department of Medical Science and Cardiorenal Medicine, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
2
Department of Nursing, Graduate School of Medicine, Yokohama City University, Yokohama 236-0004, Japan
*
Author to whom correspondence should be addressed.
Academic Editors: Anastasia Susie Mihailidou, Jan Danser, Sadayoshi Ito, Fumitoshi Satoh and Akira Nishiyama
Received: 29 January 2017 / Revised: 12 April 2017 / Accepted: 8 June 2017 / Published: 14 June 2017
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Abstract

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. View Full-Text
Keywords: Nedd4-2; cardiac ion channels; salt sensitivity; hypertension; cardio-renal syndrome; cardiovascular disease Nedd4-2; cardiac ion channels; salt sensitivity; hypertension; cardio-renal syndrome; cardiovascular disease
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Minegishi, S.; Ishigami, T.; Kawamura, H.; Kino, T.; Chen, L.; Nakashima-Sasaki, R.; Doi, H.; Azushima, K.; Wakui, H.; Chiba, Y.; Tamura, K. An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities. Int. J. Mol. Sci. 2017, 18, 1268.

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