G-CSF upregulates myocardial akt and improves function of the hearts with established heart failure due to large old myocardial infarction

Abstract We recently reported the beneficial effects of granulocyte colony-stimulating factor (G-CSF) that was started on the next day of acute myocardial infarction (MI) upon post-infarct ventricular remodeling and heart failure. However, the effect of G-CSF is unknown on the hearts with established heart failure due to old large MI. In the present study, we examined the potential therapeutic effects of G-CSF on post-infarct ventricular remodeling and heart failure at the chronic stage. To the mice with 12 week-old MI showing marked ventricular remodeling and established heart failure, G-CSF (10 microg/kg/day) was subcutaneous injected for 5 days/week for 4 weeks. According to echocardiography and hemodynamic measurement, the G-CSF treated group showed significantly alleviated left ventricular remodeling and dysfunction at 16 weeks post-infarction, compared with the distilled water-treated control group. Immunohistochemically, G-CSF receptor was overexpressed on plasma membrane of the surviving cardiomyocytes of hearts with old MI. Western blot analysis of cardiac tissues revealed a significant up-regulation of Akt and phospho-Akt in the G-CSF-treated group. However, in the other set of experiments using chimera mice transplanted GFP-positive bone marrow beforehand, no GFP-positive, bone marrow-derived cardiomyocytes was found in each group. The present findings may imply a novel therapeutic strategy against post-infarct heart failure, which is applicable during the chronic stage of MI.