Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/Akt pathway in canine hearts.
OBJECTIVE
Recent studies suggest that G-CSF prevents cardiac remodeling following myocardial infarction (MI) likely through regeneration of the myocardium and coronary vessels. However, it remains unclear whether G-CSF administered at the onset of reperfusion prevents ischemia/reperfusion injury in the acute phase. We investigated acute effects of G-CSF on myocardial infarct size and the incidence of lethal arrhythmia and evaluated the involvement of the phosphatidylinositol-3 kinase (PI3K) in the in vivo canine models.


METHODS
In open-chest dogs, left anterior descending coronary artery (LAD) was occluded for 90 minutes followed by 6 hours of reperfusion. We intravenously administered G-CSF (0.33 micro/kg/min) for 30 minutes from the onset of reperfusion. Wortmannin, a PI3K inhibitor, was selectively administered into the LAD after the onset of reperfusion.


RESULTS
G-CSF significantly (p<0.05) reduced myocardial infarct size (38.7+/-4.3% to 15.7+/-5.3%) and the incidence of ventricular fibrillation during reperfusion periods (50% to 0%) compared with the control. G-CSF enhanced Akt phospholylation in ischemic canine myocardium. Wortmannin blunted both the infarct size-limiting and anti-arrhythmic effects of G-CSF. G-CSF did not change myeloperoxidase activity, a marker of neutrophil accumulation, in the infarcted myocardium.


CONCLUSIONS
An intravenous administration of G-CSF at the onset of reperfusion attenuates ischemia/reperfusion injury through PI3K/Akt pathway in the in vivo model. G-CSF administration can be a promising candidate for the adjunctive therapy for patients with acute myocardial infarction.
Takahama
Hiroyuki
H
Department of Cardiovascular Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
Minamino
Tetsuo
T
Hirata
Akio
A
Ogai
Akiko
A
Asanuma
Hiroshi
H
Fujita
Masashi
M
Wakeno
Masakatsu
M
Tsukamoto
Osamu
O
Okada
Ken-ichiro
K
Komamura
Kazuo
K
Takashima
Seiji
S
Shinozaki
Yoshiro
Y
Mori
Hidezo
H
Mochizuki
Naoki
N
Kitakaze
Masafumi
M
D000818:Animals; D004285:Dogs; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000188:drug therapy*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism; D009195:Peroxidase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D014693:Ventricular Fibrillation / Q000188:drug therapy
D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt