title: Protection of cardiomyocytes from the hypoxia-mediated injury by a peptide targeting the activator of G-protein signaling 8.
abstract: 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.
authors.affiliation: Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Hiraoka
authors.affiliation: Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Miho
authors.initials: M
authors.lastname: Sakima
authors.affiliation: Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
authors.forename: Abdullah Al
authors.initials: AA
authors.lastname: Mamun
authors.affiliation: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Yamane
authors.affiliation: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects*; D044388:GTP-Binding Protein gamma Subunits / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D017202:Myocardial Ischemia / Q000517:prevention & control; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D018031:Connexin 43; C508124:Fndc1 protein, rat; D044388:GTP-Binding Protein gamma Subunits; D047908:Intracellular Signaling Peptides and Proteins; D010455:Peptides