Effects of Granulocyte Colony-Stimulating Factor on Diabetic cardiomyopathy in Otsuka Long-Evans Tokushima Fatty Rats

Abstract

Background: In recent studies, granulocyte colony-stimulating factor (G-CSF) was shown to improve cardiac function in myocardial infarction and non-ischemic cardiomyopathies, including diabetic cardiomyopathy. The mechanisms of these beneficial effects of G-CSF are not yet fully understood. Objective: To investigate the mechanisms of action of G-CSF on diabetic cardiomyopathy in a rat model of type 2 diabetes. Materials and Methods: 17-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 μg/kg/day) or with saline (n = 6 in each group). Serial echocardiographic examinations were performed before and 4 weeks after treatment. We measured expression of the G-CSF receptor (GCSFR), and of receptor of advanced glycation end products (RAGE), TGFβ1, and Bcl-2, as well as the extent of fibrosis and apoptosis in the myocardium. Results: G-CSF treatment significantly improved cardiac diastolic function in the serial echocardiography assessments. Expression of G-CSFR was confirmed in diabetic hearts and was up-regulated by G-CSF treatment. G-CSF-treated OLETF rats had reduced RAGE mRNA levels compared to the control rats. In addition, G-CSF increased the expression of Bcl-2, consistent with the reduced apoptosis. Conclusions: Suppression of RAGE and up-regulation of Bcl-2 expression in the diabetic myocardium appears to contribute to the cardioprotective effects of G-CSF. G-CSFR is down-regulated in the diabetic myocardium, and its expression is stimulated by G-CSF. G-CSF may be beneficial in the treatment of diabetic cardiomyopathy by virtue of its anti-fibrotic and anti-apoptotic effects.