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...
Autores principales: | , , , , , , , , , , |
---|---|
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 |