Cargando…

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

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 vol...

Descripción completa

Detalles Bibliográficos
Autores principales: Minegishi, Shintaro, Ishigami, Tomoaki, Kawamura, Hisho, Kino, Tabito, Chen, Lin, Nakashima-Sasaki, Rie, Doi, Hiroshi, Azushima, Kengo, Wakui, Hiromichi, Chiba, Yumi, Tamura, Kouichi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486090/
https://www.ncbi.nlm.nih.gov/pubmed/28613240
http://dx.doi.org/10.3390/ijms18061268
_version_ 1783246198963961856
author Minegishi, Shintaro
Ishigami, Tomoaki
Kawamura, Hisho
Kino, Tabito
Chen, Lin
Nakashima-Sasaki, Rie
Doi, Hiroshi
Azushima, Kengo
Wakui, Hiromichi
Chiba, Yumi
Tamura, Kouichi
author_facet Minegishi, Shintaro
Ishigami, Tomoaki
Kawamura, Hisho
Kino, Tabito
Chen, Lin
Nakashima-Sasaki, Rie
Doi, Hiroshi
Azushima, Kengo
Wakui, Hiromichi
Chiba, Yumi
Tamura, Kouichi
author_sort Minegishi, Shintaro
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5486090
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-54860902017-06-29 An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities Minegishi, Shintaro Ishigami, Tomoaki Kawamura, Hisho Kino, Tabito Chen, Lin Nakashima-Sasaki, Rie Doi, Hiroshi Azushima, Kengo Wakui, Hiromichi Chiba, Yumi Tamura, Kouichi Int J Mol Sci Article 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. MDPI 2017-06-14 /pmc/articles/PMC5486090/ /pubmed/28613240 http://dx.doi.org/10.3390/ijms18061268 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Minegishi, Shintaro
Ishigami, Tomoaki
Kawamura, Hisho
Kino, Tabito
Chen, Lin
Nakashima-Sasaki, Rie
Doi, Hiroshi
Azushima, Kengo
Wakui, Hiromichi
Chiba, Yumi
Tamura, Kouichi
An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title_full An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title_fullStr An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title_full_unstemmed An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title_short An Isoform of Nedd4-2 Plays a Pivotal Role in Electrophysiological Cardiac Abnormalities
title_sort isoform of nedd4-2 plays a pivotal role in electrophysiological cardiac abnormalities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5486090/
https://www.ncbi.nlm.nih.gov/pubmed/28613240
http://dx.doi.org/10.3390/ijms18061268
work_keys_str_mv AT minegishishintaro anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT ishigamitomoaki anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT kawamurahisho anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT kinotabito anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT chenlin anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT nakashimasasakirie anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT doihiroshi anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT azushimakengo anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT wakuihiromichi anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT chibayumi anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT tamurakouichi anisoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT minegishishintaro isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT ishigamitomoaki isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT kawamurahisho isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT kinotabito isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT chenlin isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT nakashimasasakirie isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT doihiroshi isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT azushimakengo isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT wakuihiromichi isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT chibayumi isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities
AT tamurakouichi isoformofnedd42playsapivotalroleinelectrophysiologicalcardiacabnormalities