Acceleration of the Healing Process and Myocardial Regeneration May Be Important as a Mechanism of Improvement of Cardiac Function and Remodeling by Postinfarction Granulocyte Colony–Stimulating Factor Treatment

TLDR

Granulocyte colony‑stimulating factor (G‑CSF) has been suggested to improve cardiac function after myocardial infarction, but the underlying mechanisms remain unclear. The study investigated whether G‑CSF improves cardiac function and remodeling by accelerating the healing process and promoting myocardial regeneration. In a rabbit model of 30‑minute coronary occlusion and reperfusion, rabbits received saline or 10 µg kg⁻¹ day⁻¹ of recombinant G‑CSF subcutaneously from days 1–5 post‑MI. G‑CSF treatment produced smaller left‑ventricular dimensions, higher ejection fraction, thicker infarct walls, accelerated necrotic tissue clearance, increased macrophages and MMP‑1/9, reduced granulation and scar tissue, and greater surviving myocardial tissue and cardiomyocyte numbers, indicating accelerated healing and regeneration.

Abstract

We investigated whether the improvement of cardiac function and remodeling after myocardial infarction (MI) by granulocyte colony-stimulating factor (G-CSF) relates to acceleration of the healing process, in addition to myocardial regeneration.In a 30-minute coronary occlusion and reperfusion rabbit model, saline (S) or 10 microg x kg(-1) x d(-1) of human recombinant G-CSF (G) was injected subcutaneously from 1 to 5 days after MI. Smaller left ventricular (LV) dimension, increased LV ejection fraction, and thicker infarct-LV wall were seen in G at 3 months after MI. At 2, 7, and 14 days and 3 months after MI, necrotic tissue areas were 14.2+/-1.5/13.4+/-1.1, 0.4+/-0.1/1.8+/-0.5*, 0/0, and 0/0 mm2 x slice(-1) x kg(-1), granulation areas 0/0, 4.0+/-0.7/8.5+/-1.0*, 3.9+/-0.8/5.7+/-0.7,* and 0/0 mm2 x slice(-1) x kg(-1), and scar areas 0/0, 0/0, 0/0, and 4.2+/-0.5/7.9+/-0.9* mm2 x slice(-1) x kg(-1) in G and S, respectively (*P<0.05, G versus S). Clear increases of macrophages and of matrix metalloproteinases (MMP) 1 and 9 were seen in G at 7 days after MI. This suggests that G accelerates absorption of necrotic tissues via increase of macrophages and reduces granulation and scar tissues via expression of MMPs. Meanwhile, surviving myocardial tissue areas within the risk areas were significantly increased in G despite there being no difference in LV weight, LV wall area, or cardiomyocyte size between G and S. Confocal microscopy revealed significant increases of cardiomyocytes with positive 3,3,3',3'-tetramethylindocarbocyanine perchlorate and positive troponin I in G, suggesting enhanced myocardial regeneration by G.The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.