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Updated: Jul 7, 2026
Post-Myocardial Infarction Heart Failure in Closed-chest Coronary Occlusion/Reperfusion Model in Göttingen Minipigs and Landrace Pigs
Published on: April 17, 2021
Effect of a long-term treatment with a low-dose granulocyte colony-stimulating factor on post-infarction process in
Hideshi Okada1, Genzou Takemura, Yiwen Li
1Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan.
Insights
Long-term, low-dose granulocyte colony-stimulating factor (G-CSF) treatment mitigates cardiac remodeling and dysfunction after myocardial infarction (MI). This therapy, possibly via STAT3, reduces fibrosis and preserves cardiomyocytes, suggesting a feasible clinical approach.
Area of Science:
- Cardiovascular Research
- Regenerative Medicine
- Pharmacology
Background:
- Granulocyte colony-stimulating factor (G-CSF) shows potential benefits post-myocardial infarction (MI).
- Mechanisms and optimal administration strategies for G-CSF in MI recovery remain unclear.
- Investigating long-term, low-dose G-CSF effects is crucial for clinical translation.
Purpose of the Study:
- To evaluate the effects of a 4-week, low-dose G-CSF treatment initiated 1 day post-MI.
- To elucidate the underlying molecular mechanisms, including STAT3 and Akt signaling pathways.
- To assess the impact on cardiac remodeling, function, fibrosis, and cardiomyocyte health.
Main Methods:
- Myocardial infarction induced in mice via left coronary ligation.
- Daily subcutaneous administration of G-CSF (10 microg/kg/day) for 4 weeks post-MI.
- Assessment of cardiac function, histology (fibrosis, scar size), cardiomyocyte changes, apoptosis, and molecular signaling (STAT3, Akt, GATA-4, MHC, MMPs).
- Pharmacological inhibition of STAT3 (Parthenolide) and Akt (Wortmannin) to determine pathway involvement.
Main Results:
- G-CSF treatment significantly reduced cardiac remodeling and improved cardiac dysfunction post-MI.
- Histological analysis revealed smaller infarct scars, reduced fibrosis, and increased vascularization in G-CSF treated hearts.
- Beneficial effects correlated with STAT3 activation, increased GATA-4, myosin heavy chain, and MMPs, but not Akt activation for angiogenesis.
- STAT3 inhibition abolished G-CSF benefits, while Akt inhibition did not impact overall recovery despite reduced vascularization.
Conclusions:
- Long-term, low-dose G-CSF administration confers significant benefits on post-MI cardiac remodeling and function.
- The protective effects are primarily mediated through STAT3-dependent pathways, reducing cardiomyocyte degeneration and fibrosis.
- G-CSF does not appear to act via cardiomyocyte apoptosis reduction or Akt-mediated angiogenesis.
- Findings suggest a potentially feasible and effective clinical strategy for G-CSF administration in post-MI patients.
Abstract:
Although beneficial effects of granulocyte colony-stimulating factor (G-CSF) have been demonstrated on post-myocardia infarction (MI) process, the mechanisms and feasibility are not fully agreed yet. We investigated effects of a long-term treatment with a low-dose G-CSF started 1 day after the onset of MI, on post-infarction process. One day after being made MI by left coronary ligation, mice were given G-CSF (10 microg/kg/day) for 4 weeks. The G-CSF treatment resulted in a significant mitigation of cardiac remodelling and dysfunction. In the G-CSF-treated hearts, the infarcted scar was smaller with less fibrosis and abundant vessels while in the non-infarcted area, hypertrophic cardiomyocytes with attenuated degenerative changes and reduced fibrosis were apparent. These effects were accompanied by activation of signal transducer and activator of transcription 3 (STAT3) and Akt and also by up-regulation of GATA-4, myosin heavy chain and matrix metalloproteinases-2 and -9. Apoptosis of cardiomyocytes appeared insignificant at any stages. Parthenolide, a STAT3 inhibitor, completely abolished the beneficial effects of G-CSF on cardiac function and remodelling with loss of effect on both anti-cardiomyocyte degeneration and anti-fibrosis. In contrast, wortmannin, an Akt inhibitor, did not affect G-CSF-induced benefits despite cancelling vessel increase. In conclusion, treatment with G-CSF at a small dose but for a long duration beneficially affects the post-infarction process possibly through STAT3-mediated anti-cardiomyocyte degeneration and anti-fibrosis, but not through anti-cardiomyocyte apoptosis or Akt-mediated angio-genesis. The findings may also imply a more feasible way of G-CSF administration in the clinical settings.
