Effects of granulocyte-colony stimulating factor (G-CSF) on diabetic cardiomyopathy in Otsuka Long-Evans Tokushima Fatty rats

Abstract

BackgroundDiabetic cardiomyopathy (CMP) is a common and disabling disease in diabetic patients, however no effective treatments have been developed. Although granulocyte-colony stimulating factor (G-CSF) improves heart function in myocardial infarction, its effect on non-ischemic CMP such as diabetic CMP is unknown. In the present study, we investigated the effects of G-CSF on diabetic CMP in a rat model of type II diabetes.MethodsTwenty 7-week-old male Otsuka Long-Evans Tokushima Fatty (OLETF: a rat model of diabetes) rats and 10 male Long-Evans Tokushima Otsuka (LETO: normal controls) rats were used. All of the LETO and 8 OLETF rats were fed on tap water while the rest were fed on sucrose-containing water. After 10 weeks, saline or recombinant human G-CSF (100 μg/kg/day) was injected intraperitoneally for 5 days. Blood levels of glucose, total cholesterol and triglyceride, and Doppler echocardiograms for diastolic dysfunction were obtained just before and 4 weeks after the saline or G-CSF treatment. Light microscopy, electron microscopy (EM) and immunohistochemistry for transforming growth factor-β were employed to examine myocardial histology 4 weeks after the saline or G-CSF treatment.ResultsDiastolic dysfunction developed at 17 weeks (before the saline or G-CSF treatment) in the OLETF rats whether or not they were fed sucrose water, but were more severe in those fed sucrose water. Four weeks after saline or G-CSF treatment, diastolic function had recovered in the G-CSF-treated group regardless of sucrose water feeding, and perivascular and/or interstitial fibrosis in the G-CSF-treated group had decreased significantly. TGF-β immunoreactivity in the interstitial and perivascular tissue was also reduced in the G-CSF-treated group, and EM studies revealed less severe disruption of myofilaments and mitochondrial cristae, and decreased collagen deposition.ConclusionsG-CSF can ameliorate cardiac diastolic dysfunction and morphological damage, especially fibrosis of the myocardium, in OLETF rats with diabetic CMP.

Alpha-lipoic acid attenuates cardiac fibrosis in Otsuka Long-Evans Tokushima Fatty rats

“…Furthermore, adiponectin supplementation improved concentric cardiac hypertrophy in adiponectin-deficient mice [9]. Recent study showed that recombinant human granulocyte-colony stimulating factor (G-CSF) ameliorates cardiac diastolic dysfunction and fibrosis in OLETF rats [47]. Although cardiac hypertrophy was not detected in the OLETF rat model used in this study, recent study showed that ALA (100 mg/kg/day) reversed impairment of systolic function in STZ-treated diabetic rats compared to controls [21].…”

Bone Marrow-Derived Stem Cells: a Mixed Blessing in the Multifaceted World of Diabetic Complications

“…Cytokines and growth factors could be used to potentiate stem cell mobilization and homing to the myocardium. Improved mobilization with granulocyte colony-stimulating factor (G-CSF) ameliorates the rat model of CDM decreasing perivascular interstitial fibrosis [ 37 ]. Our recent study in BM cells from infarcted patients demonstrated that SDF-1 directed migration enriches for cells with increased healing activity [ 38 ].…”

G-CSF Prevents Progression of Diabetic Nephropathy in Rat

“…For example, one study showed that G-CSF increased angiogenesis and reversed ischemic damage in the brain [8]. In other studies, G-CSF protected against renal tubular injury induced by adriamycin [9] and against hepatic steatosis [10], as well as diabetic cardiomyopathy in rats [11]. Flaquer M, et al demonstrated that the combination of hepatocyte growth factor gene therapy with hematopoietic stem cell mobilization by G-CSF may contribute to renal tissue repair and regeneration in diabetes- induced mice [12].…”