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Postconditioning effect of granulocyte colony-stimulating factor is mediated through activation of risk pathway and opening of the mitochondrial KATP channels

Authors :
Shinya Minatoguchi
Shohei Sumi
Yoshihisa Yamada
Masamitsu Iwasa
Hiroyuki Kobayashi
Takahiko Yamaki
Takuma Aoyama
Hiroaki Ushikoshi
Shinji Yasuda
Arihiro Hattori
Genzou Takemura
Kazuhiko Nishigaki
Source :
American Journal of Physiology-Heart and Circulatory Physiology. 299:H1174-H1182
Publication Year :
2010
Publisher :
American Physiological Society, 2010.

Abstract

Granulocyte colony-stimulating factor (G-CSF) has been reported to improve cardiac function after myocardial infarction. However, whether postinfarct acute effect of G-CSF is mediated through the same signaling pathways as those of ischemic postconditioning is still unclear. We examined the postinfarct acute effect of G-CSF on myocardial infarct size and its precise molecular mechanism. Japanese white rabbits underwent 30 min of ischemia and 48 h of reperfusion. Rabbits were intravenously injected 10 μg/kg of G-CSF (G-CSF group) or saline (control group) immediately after reperfusion. The wortmannin + G-CSF, PD-98059 + G-CSF, Nω-nitro-l-arginine methyl ester (l-NAME) + G-CSF, and 5-hydroxydecanoic acid sodium salt (5-HD) + G-CSF groups were respectively injected with wortmannin (0.6 mg/kg), PD-98059 (0.3 mg/kg), l-NAME (10 mg/kg), and 5-HD (5 mg/kg) 5 min before G-CSF administration. Myocardial infarct size was calculated as a percentage of the risk area of the left ventricle. Western blot analysis was performed to examine the signals such as protein kinase B (Akt), extracellular signal-regulated protein kinase (ERK), eNOS, p70S6 kinase (p70S6K), and glycogen synthase kinase-3β (GSK3β) in the ischemic myocardium after 48 h of reperfusion. The infarct size was significantly smaller in the G-CSF group (26.7 ± 2.7%) than in the control group (42.3 ± 4.6%). The infarct size-reducing effect of G-CSF was completely blocked by wortmannin (44.7 ± 4.8%), PD-98059 (38.3 ± 3.9%), l-NAME (42.1 ± 4.2%), and 5-HD (42.5 ± 1.7%). Wortmannin, PD-98059, l-NAME, or 5-HD alone did not affect the infarct size. Western blotting showed higher myocardial expression of phospho-Akt, phospho-ERK, phosho-eNOS, phosho-p70S6K, and phosho-GSK3β at 10 min and 48 h after reperfusion in the G-CSF group than in the control group. In conclusion, postreperfusion G-CSF administration reduces myocardial infarct size via activation of phosphatidylinositol 3-kinase-Akt and ERK prosurvival signaling pathways and their downstream targets eNOS, p70S6 kinase, GSK3β, and mitochondrial ATP-dependent K+ channel.

Details

ISSN :
15221539 and 03636135
Volume :
299
Database :
OpenAIRE
Journal :
American Journal of Physiology-Heart and Circulatory Physiology
Accession number :
edsair.doi.dedup.....881d880b7f4cc68d7617bb5211a7f6e4
Full Text :
https://doi.org/10.1152/ajpheart.00116.2010