Granulocyte colony stimulating factor/macrophage colony stimulating factor improves postinfarct ventricular function by suppression of border zone remodelling in rats

Abstract

1. The aim of the present study was to examine the effects of mobilization of bone marrow cells by granulocyte colony stimulating factor (G-CSF) and macrophage colony stimulating factor (M-CSF) on ventricular function after myocardial infarction (MI). 2. After ligation of the left coronary artery, rats were divided into a vehicle control group (MI group) and a CSF-treated group (MI-CSF group). Rats in the MI-CSF group received a combination of G-CSF (50 microg/kg per day) and M-CSF (10(6) IU/kg per day) for 5 days after MI. Two weeks after MI, hearts were isolated and perfused with a Krebs' buffer and their functional responses to step-wise elevation of left ventricular end-diastolic pressure (LVEDP) were assessed. In histological analysis, proliferating cells and bone marrow-derived cells were identified by antibodies against Ki-67 and c-kit and organization of collagen was examined by picrosirius red staining. The mRNA levels of transforming growth factor (TGF)-beta(1), collagen type I and collagen type III were measured by quantitative reverse transcription-polymerase chain reaction. 3. Numbers of Ki-67- and c-kit-positive cells in the infarct border zone after MI were increased by CSF treatment, but few of those cells were stained by anti-alpha-sarcomeric actin. The levels in mRNA of TGF-beta1 and collagen type I in the infarct border zone were higher in the CSF-treated group compared with the MI group. Although CSF treatment did not reduce ventricular hypertrophy or infarct size at 2 weeks after MI, it did significantly improved the response of left ventricular developed pressure to step-wise elevation of LVEDP. This effect was mimicked by treatment with M-CSF alone. The functional improvement by CSF treatment was correlated with suppression of enlargement of the infarct-non-infarct border associated with infarct expansion. Collagen fibres in the border zone were thicker and orientated more orderly in the CSF-treated group than in the untreated group. 4. The results suggest that G-CSF/M-CSF treatment improves contractile function of the ventricle after infarction, presumably by acceleration of infarct repair and suppression of remodelling in the border zone.