Granulocyte colony-stimulating factor exacerbates cardiac fibrosis after myocardial infarction in a rat model of permanent occlusion.
OBJECTIVE
Controversy exists regarding the effects of granulocyte colony-stimulating factor (G-CSF) on post-infarction remodelling, which is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The aim of this study was to investigate the impact of G-CSF administration on cardiac MMP/TIMP ratios and long-term remodelling in a rat model of acute myocardial infarction (MI).


RESULTS
Sprague-Dawley rats underwent coronary ligation to produce MI. Rats surviving the MI for 3 h were randomized to receive G-CSF (50 microg/kg/day for 5 consecutive days, n = 16) or saline (n = 10). Sham-operated animals received no treatment (n = 10). G-CSF injection significantly increased circulating white blood cells, neutrophils, and monocytes. Western blotting revealed that the ratios of MMP-2/TIMP-1 and MMP-9/TIMP-1 were significantly decreased in the infarcted myocardium. At 3 months, echocardiographic and haemodynamic examinations showed that the G-CSF treatment induced left ventricular (LV) enlargement and dysfunction. Histological analysis revealed that the extent of myocardial fibrosis and infarct size were larger in the G-CSF group than in the Saline group. Furthermore, G-CSF treated animals showed a significantly lower post-MI survival during the study period.


CONCLUSIONS
Decrease of cardiac MMP/TIMP ratios by G-CSF after infarction may be important as a mechanism in promotion of myocardial fibrosis, which further facilitates infarct expansion and LV dysfunction.
Cheng
Zhaokang
Z
Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Science, Nankai University, Tianjin 300071, China.
Ou
Lailiang
L
Liu
Yi
Y
Liu
Xiaolei
X
Li
Fei
F
Sun
Bin
B
Che
Yongzhe
Y
Kong
Deling
D
Yu
Yaoting
Y
Steinhoff
Gustav
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D054059:Coronary Occlusion / Q000150:complications*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects* / Q000494:pharmacology*; D006352:Heart Ventricles / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D009000:Monocytes / Q000473:pathology; D009203:Myocardial Infarction / Q000209:etiology* / Q000378:metabolism / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009504:Neutrophils / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014463:Ultrasonography; D020257:Ventricular Remodeling / Q000187:drug effects
D019715:Tissue Inhibitor of Metalloproteinase-1; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9