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

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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.

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Abbreviations

VF:

ventricular fibrillation

G-CSF:

granulocyte colony-stimulating factor

WTMN:

wortmannin

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, National Cardiovascular Center, Suita, 565-8565, Osaka, Japan

    Hiroyuki Takahama, Akiko Ogai, Hiroshi Asanuma, Masakatsu Wakeno, Kazuo Komamura, Hidezo Mori & Masafumi Kitakaze

  2. Department of Structural Analysis, National Cardiovascular Center, Suita, 565-8565, Osaka, Japan

    Hiroyuki Takahama, Masakatsu Wakeno & Naoki Mochizuki

  3. Department of Bioregulatory Medicine, Osaka University Graduate School of Medicine, Suita, 565-0871, Osaka, Japan

    Hiroyuki Takahama, Masakatsu Wakeno & Naoki Mochizuki

  4. Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, 565-0871, Osaka, Japan

    Tetsuo Minamino, Akio Hirata, Masashi Fujita, Osamu Tsukamoto, Ken-ichiro Okada & Seiji Takashima

  5. Department of Physiological Science, Tokai University School of Medicine, Isehara, 259-1193, Kanagawa, Japan

    Yoshiro Shinozaki

Authors
  1. Hiroyuki Takahama
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  2. Tetsuo Minamino
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  3. Akio Hirata
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  4. Akiko Ogai
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  5. Hiroshi Asanuma
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  10. Kazuo Komamura
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  11. Seiji Takashima
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  12. Yoshiro Shinozaki
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  13. Hidezo Mori
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  14. Naoki Mochizuki
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  15. Masafumi Kitakaze
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Corresponding author

Correspondence to Tetsuo Minamino.

Additional information

Takahama and Hirata contributed equally to this work.

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Takahama, H., Minamino, T., Hirata, A. et al. Granulocyte Colony-Stimulating Factor Mediates Cardioprotection Against Ischemia/Reperfusion Injury via Phosphatidylinositol-3-Kinase/Akt Pathway in Canine Hearts. Cardiovasc Drugs Ther 20, 159–165 (2006). https://doi.org/10.1007/s10557-006-8285-8

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  • DOI: https://doi.org/10.1007/s10557-006-8285-8

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