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PLoS One. 2014 Mar 14;9(3):e91980. doi: 10.1371/journal.pone.0091980. eCollection 2014.

Protection of cardiomyocytes from the hypoxia-mediated injury by a peptide targeting the activator of G-protein signaling 8.

Author information

1
Department of Physiology, Aichi Medical University, Nagakute, Aichi, Japan.
2
Cardiovascular Research Institute, Yokohama City University School of Medicine, Fukuura, Yokohama, Japan.
3
Department of Physiology, Tsurumi University School of Dental Medicine, Yokohama, Japan.

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.

PMID:
24632710
PMCID:
PMC3954831
DOI:
10.1371/journal.pone.0091980
[Indexed for MEDLINE]
Free PMC Article

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