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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
- 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.
- Subjects :
- Male
Cardiac function curve
medicine.medical_specialty
Nitric Oxide Synthase Type III
Physiology
Myocardial Infarction
Granulocyte
Mitochondrion
Mitochondria, Heart
Wortmannin
Glycogen Synthase Kinase 3
chemistry.chemical_compound
KATP Channels
Physiology (medical)
Internal medicine
Granulocyte Colony-Stimulating Factor
medicine
Animals
Extracellular Signal-Regulated MAP Kinases
Protein kinase B
GSK3B
Glycogen Synthase Kinase 3 beta
business.industry
Heart
Adenosine
Granulocyte colony-stimulating factor
Androstadienes
NG-Nitroarginine Methyl Ester
Endocrinology
medicine.anatomical_structure
chemistry
Reperfusion Injury
Models, Animal
Rabbits
Phosphatidylinositol 3-Kinase
Hydroxy Acids
Cardiology and Cardiovascular Medicine
business
Decanoic Acids
Proto-Oncogene Proteins c-akt
Signal Transduction
medicine.drug
Subjects
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