Document Detail

Postconditioning effect of granulocyte colony-stimulating factor is mediated through activation of risk pathway and opening of the mitochondrial KATP channels.
MedLine Citation:
PMID:  20693399     Owner:  NLM     Status:  MEDLINE    
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, N(ω)-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.
Shohei Sumi; Hiroyuki Kobayashi; Shinji Yasuda; Masamitsu Iwasa; Takahiko Yamaki; Yoshihisa Yamada; Hiroaki Ushikoshi; Arihiro Hattori; Takuma Aoyama; Kazuhiko Nishigaki; Genzou Takemura; Shinya Minatoguchi
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Publication Detail:
Type:  Journal Article     Date:  2010-08-06
Journal Detail:
Title:  American journal of physiology. Heart and circulatory physiology     Volume:  299     ISSN:  1522-1539     ISO Abbreviation:  Am. J. Physiol. Heart Circ. Physiol.     Publication Date:  2010 Oct 
Date Detail:
Created Date:  2010-10-04     Completed Date:  2010-11-30     Revised Date:  2011-11-02    
Medline Journal Info:
Nlm Unique ID:  100901228     Medline TA:  Am J Physiol Heart Circ Physiol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  H1174-82     Citation Subset:  IM    
Department of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
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MeSH Terms
Androstadienes / pharmacology
Decanoic Acids / pharmacology
Extracellular Signal-Regulated MAP Kinases / metabolism
Glycogen Synthase Kinase 3 / metabolism
Granulocyte Colony-Stimulating Factor / therapeutic use*
Heart / drug effects
Hydroxy Acids / pharmacology
KATP Channels / physiology*
Mitochondria, Heart / physiology*
Models, Animal
Myocardial Infarction / physiopathology*
NG-Nitroarginine Methyl Ester / pharmacology
Nitric Oxide Synthase Type III / metabolism
Phosphatidylinositol 3-Kinase / metabolism
Proto-Oncogene Proteins c-akt / metabolism
Reperfusion Injury / physiopathology*,  prevention & control*
Signal Transduction / physiology*
Reg. No./Substance:
0/Androstadienes; 0/Decanoic Acids; 0/Hydroxy Acids; 0/KATP Channels; 143011-72-7/Granulocyte Colony-Stimulating Factor; 19545-26-7/wortmannin; 50903-99-6/NG-Nitroarginine Methyl Ester; 624-00-0/5-hydroxydecanoic acid; EC Oxide Synthase Type III; EC 3-Kinase; EC Proteins c-akt; EC synthase kinase 3 beta; EC Signal-Regulated MAP Kinases; EC Synthase Kinase 3

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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