title: Granulocyte colony-stimulating factor mediates cardioprotection against ischemia/reperfusion injury via phosphatidylinositol-3-kinase/Akt pathway in canine hearts.
abstract: 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.
authors.affiliation: Department of Cardiovascular Medicine, National Cardiovascular Center, Suita, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Takahama
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Minamino
authors.forename: Akio
authors.initials: A
authors.lastname: Hirata
authors.forename: Akiko
authors.initials: A
authors.lastname: Ogai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asanuma
authors.forename: Masashi
authors.initials: M
authors.lastname: Fujita
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Wakeno
authors.forename: Osamu
authors.initials: O
authors.lastname: Tsukamoto
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Okada
authors.forename: Kazuo
authors.initials: K
authors.lastname: Komamura
authors.forename: Seiji
authors.initials: S
authors.lastname: Takashima
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Shinozaki
authors.forename: Hidezo
authors.initials: H
authors.lastname: Mori
authors.forename: Naoki
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
mesh_terms: 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
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D009195:Peroxidase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt