Granulocyte colony-stimulating factor exacerbates cardiac fibrosis after myocardial infarction in a rat model of permanent occlusion

Abstract

Aims: 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).

Methods and 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.

Conclusion: 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.