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Cardiovascular Drugs and Therapy

, Volume 20, Issue 3, pp 159–165 | Cite as

Granulocyte Colony-Stimulating Factor Mediates Cardioprotection Against Ischemia/Reperfusion Injury via Phosphatidylinositol-3-Kinase/Akt Pathway in Canine Hearts

  • Hiroyuki Takahama
  • Tetsuo Minamino
  • Akio Hirata
  • Akiko Ogai
  • Hiroshi Asanuma
  • Masashi Fujita
  • Masakatsu Wakeno
  • Osamu Tsukamoto
  • Ken-ichiro Okada
  • Kazuo Komamura
  • Seiji Takashima
  • Yoshiro Shinozaki
  • Hidezo Mori
  • Naoki Mochizuki
  • Masafumi Kitakaze
Basic Research

Abstract

Purpose

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 μ/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.

Conclusion

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.

Key words

G-CSF myocardial infarction ischemia-reperfusion injury ventricular fibrillation phosphatidylinositol-3 kinase Akt 

Abbreviations

VF

ventricular fibrillation

G-CSF

granulocyte colony-stimulating factor

WTMN

wortmannin

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Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Hiroyuki Takahama
    • 1
    • 2
    • 3
  • Tetsuo Minamino
    • 4
  • Akio Hirata
    • 4
  • Akiko Ogai
    • 1
  • Hiroshi Asanuma
    • 1
  • Masashi Fujita
    • 4
  • Masakatsu Wakeno
    • 1
    • 2
    • 3
  • Osamu Tsukamoto
    • 4
  • Ken-ichiro Okada
    • 4
  • Kazuo Komamura
    • 1
  • Seiji Takashima
    • 4
  • Yoshiro Shinozaki
    • 5
  • Hidezo Mori
    • 1
  • Naoki Mochizuki
    • 2
    • 3
  • Masafumi Kitakaze
    • 1
  1. 1.Department of Cardiovascular MedicineNational Cardiovascular CenterOsakaJapan
  2. 2.Department of Structural AnalysisNational Cardiovascular CenterOsakaJapan
  3. 3.Department of Bioregulatory MedicineOsaka University Graduate School of MedicineOsakaJapan
  4. 4.Department of Cardiovascular MedicineOsaka University Graduate School of MedicineOsakaJapan
  5. 5.Department of Physiological ScienceTokai University School of MedicineKanagawaJapan

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