Cargando…

Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8

Signaling via heterotrimeric G-protein is involved in the development of human diseases including ischemia-reperfusion injury of the heart. We previously identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which regulates Gβγ signaling and plays a key rol...

Descripción completa

Detalles Bibliográficos
Autores principales: Sato, Motohiko, Hiraoka, Masahiro, Suzuki, Hiroko, Sakima, Miho, Mamun, Abdullah Al, Yamane, Yukiko, Fujita, Takayuki, Yokoyama, Utako, Okumura, Satoshi, Ishikawa, Yoshihiro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954831/
https://www.ncbi.nlm.nih.gov/pubmed/24632710
http://dx.doi.org/10.1371/journal.pone.0091980
_version_ 1782307510907043840
author Sato, Motohiko
Hiraoka, Masahiro
Suzuki, Hiroko
Sakima, Miho
Mamun, Abdullah Al
Yamane, Yukiko
Fujita, Takayuki
Yokoyama, Utako
Okumura, Satoshi
Ishikawa, Yoshihiro
author_facet Sato, Motohiko
Hiraoka, Masahiro
Suzuki, Hiroko
Sakima, Miho
Mamun, Abdullah Al
Yamane, Yukiko
Fujita, Takayuki
Yokoyama, Utako
Okumura, Satoshi
Ishikawa, Yoshihiro
author_sort Sato, Motohiko
collection PubMed
description Signaling via heterotrimeric G-protein is involved in the development of human diseases including ischemia-reperfusion injury of the heart. We previously identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which regulates Gβγ signaling and plays a key role in the hypoxia-induced apoptosis of cardiomyocytes. Here, we attempted to intervene in the AGS8-Gβγ signaling process and protect cardiomyocytes from hypoxia-induced apoptosis with a peptide that disrupted the AGS8-Gβγ interaction. Synthesized AGS8-peptides, with amino acid sequences based on those of the Gβγ-binding domain of AGS8, successfully inhibited the association of AGS8 with Gβγ. The AGS8-peptide effectively blocked hypoxia-induced apoptosis of cardiomyocytes, as determined by DNA end-labeling and an increase in cleaved caspase-3. AGS8-peptide also inhibited the change in localization/permeability of channel protein connexin 43, which was mediated by AGS8-Gβγ under hypoxia. Small compounds that inhibit a wide range of Gβγ signals caused deleterious effects in cardiomyocytes. In contrast, AGS8-peptide did not cause cell damage under normoxia, suggesting an advantage inherent in targeted disruption of the AGS8-Gβγ signaling pathway. These data indicate a pivotal role for the interaction of AGS8 with Gβγ in hypoxia-induced apoptosis of cardiomyocytes, and suggest that targeted disruption of the AGS8-Gβγ signal provides a novel approach for protecting the myocardium against ischemic injury.
format Online
Article
Text
id pubmed-3954831
institution National Center for Biotechnology Information
language English
publishDate 2014
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-39548312014-03-18 Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8 Sato, Motohiko Hiraoka, Masahiro Suzuki, Hiroko Sakima, Miho Mamun, Abdullah Al Yamane, Yukiko Fujita, Takayuki Yokoyama, Utako Okumura, Satoshi Ishikawa, Yoshihiro PLoS One Research Article Signaling via heterotrimeric G-protein is involved in the development of human diseases including ischemia-reperfusion injury of the heart. We previously identified an ischemia-inducible G-protein activator, activator of G-protein signaling 8 (AGS8), which regulates Gβγ signaling and plays a key role in the hypoxia-induced apoptosis of cardiomyocytes. Here, we attempted to intervene in the AGS8-Gβγ signaling process and protect cardiomyocytes from hypoxia-induced apoptosis with a peptide that disrupted the AGS8-Gβγ interaction. Synthesized AGS8-peptides, with amino acid sequences based on those of the Gβγ-binding domain of AGS8, successfully inhibited the association of AGS8 with Gβγ. The AGS8-peptide effectively blocked hypoxia-induced apoptosis of cardiomyocytes, as determined by DNA end-labeling and an increase in cleaved caspase-3. AGS8-peptide also inhibited the change in localization/permeability of channel protein connexin 43, which was mediated by AGS8-Gβγ under hypoxia. Small compounds that inhibit a wide range of Gβγ signals caused deleterious effects in cardiomyocytes. In contrast, AGS8-peptide did not cause cell damage under normoxia, suggesting an advantage inherent in targeted disruption of the AGS8-Gβγ signaling pathway. These data indicate a pivotal role for the interaction of AGS8 with Gβγ in hypoxia-induced apoptosis of cardiomyocytes, and suggest that targeted disruption of the AGS8-Gβγ signal provides a novel approach for protecting the myocardium against ischemic injury. Public Library of Science 2014-03-14 /pmc/articles/PMC3954831/ /pubmed/24632710 http://dx.doi.org/10.1371/journal.pone.0091980 Text en © 2014 Sato et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Sato, Motohiko
Hiraoka, Masahiro
Suzuki, Hiroko
Sakima, Miho
Mamun, Abdullah Al
Yamane, Yukiko
Fujita, Takayuki
Yokoyama, Utako
Okumura, Satoshi
Ishikawa, Yoshihiro
Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title_full Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title_fullStr Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title_full_unstemmed Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title_short Protection of Cardiomyocytes from the Hypoxia-Mediated Injury by a Peptide Targeting the Activator of G-Protein Signaling 8
title_sort protection of cardiomyocytes from the hypoxia-mediated injury by a peptide targeting the activator of g-protein signaling 8
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3954831/
https://www.ncbi.nlm.nih.gov/pubmed/24632710
http://dx.doi.org/10.1371/journal.pone.0091980
work_keys_str_mv AT satomotohiko protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT hiraokamasahiro protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT suzukihiroko protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT sakimamiho protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT mamunabdullahal protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT yamaneyukiko protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT fujitatakayuki protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT yokoyamautako protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT okumurasatoshi protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8
AT ishikawayoshihiro protectionofcardiomyocytesfromthehypoxiamediatedinjurybyapeptidetargetingtheactivatorofgproteinsignaling8