Granulocyte-Colony Stimulating Factor Reduces Cardiomyocyte Apoptosis and Ameliorates Diastolic Dysfunction in Otsuka Long-Evans Tokushima Fatty Rats

Abstract

In recent studies, granulocyte-colony stimulating factor (G-CSF) was shown to improve cardiac function in myocardial infarction and non-ischemic cardiomyopathies. The mechanisms of these beneficial effects of G-CSF in diabetic cardiomyopathy are not yet fully understood. Therefore, we investigated the mechanisms of action of G-CSF on diabetic cardiomyopathy in a rat model of type 2 diabetes.Seventeen-week-old OLETF (Otsuka Long Evans Tokushima Fatty) diabetic rats and LETO (Long Evans Tokushima Otuska) rats were randomized to treatment with 5 days of G-CSF (100 mu g/kg/day) or with saline. Cardiac function was evaluated by serial echocardiography performed before and 4 weeks after treatment. We measured expression of the G-CSF receptor (GCSFR) and Bcl-2, as well as the extent of apoptosis in the myocardium.G-CSF treatment significantly improved cardiac diastolic function in the serial echocardiography assessments. Expression of G-CSFR was down-regulated in the diabetic myocardium (0.03 +/- 0.12 % vs. 1 +/- 0.15 %, p < 0.05), and its expression was stimulated by G-CSF treatment (0.03 +/- 0.12 % vs. 0.42 +/- 0.06 %, p < 0.05). In addition, G-CSF treatment increased the expression of Bcl-2 in the diabetic myocardium (0.69 +/- 0.06 % vs. 0.26 +/- 0.11 %, p < 0.05), consistent with the reduced cardiomyocyte apoptosis (9.38 +/- 0.67 % vs. 17.28 +/- 2.16 %, p < 0.05).Our results suggest that G-CSF might have a cardioprotective effect in diabetic cardiomyopathy through up-regulation of G-CSFR, attenuation of apoptosis by up-regulation of Bcl-2 expression, and glucose-lowering effect. Our findings support the therapeutic potential of G-CSF in diabetic cardiomyopathy.