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.

Abstract

BACKGROUND:

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.

METHODS AND RESULTS:

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.

CONCLUSIONS:

The acceleration of the healing process and myocardial regeneration may play an important role for the beneficial effect of post-MI G-CSF treatment.

• Authors: Shinya Minatoguchi, Genzou Takemura, Xue-Hai Chen, Ningyuan Wang, Yoshihiro Uno, Masahiko Koda, Masazumi Arai, Yu Misao, Chuanjiang Lu, Koji Suzuki, Kazuko Goto, Ai Komada, Tomoyuki Takahashi, Kenichiro Kosai, Takako Fujiwara, Hisayoshi Fujiwara
• Journal: Circulation (Circulation) Vol. 109 Issue 21 Pg. 2572-80 (Jun 01 2004) ISSN: 1524-4539 [Electronic] United States
• PMID: 15123535 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• Granulocyte Colony-Stimulating Factor
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase 1

Topics

• Animals
• Cell Size (drug effects)
• Cicatrix (etiology, pathology, prevention & control)
• Drug Evaluation, Preclinical
• Echocardiography
• Granulation Tissue (pathology)
• Granulocyte Colony-Stimulating Factor (pharmacology, therapeutic use)
• Heart (drug effects)
• Macrophages (physiology)
• Matrix Metalloproteinase 1 (analysis)
• Matrix Metalloproteinase 9 (analysis)
• Microscopy, Confocal
• Myocardial Infarction (drug therapy, pathology, physiopathology)
• Myocardium (enzymology, pathology)
• Myocytes, Cardiac (drug effects)
• Rabbits
• Recombinant Proteins (pharmacology, therapeutic use)
• Regeneration (drug effects)
• Ventricular Remodeling (drug effects)