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