Granulocyte-colony stimulating factor reduces cardiomyocyte apoptosis and ameliorates diastolic dysfunction in Otsuka Long-Evans Tokushima Fatty rats.
BACKGROUND
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.


METHODS
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 μg/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.


RESULTS
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).


CONCLUSIONS
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.
Cardiology division, Department of Internal Medicine, Hanyang University College of Medicine, 222 Wangsipri Street, Sungdong-gu, Seoul, 133-792, Republic of Korea.
Jeong Hun
JH
Shin
Young-Hyo
YH
Lim
Yi-Sun
YS
Song
Byung-Im
BI
So
Jun-Young
JY
Park
Cheng-Hu
CH
Fang
Yonggu
Y
Lee
Hyuck
H
Kim
Kyung-Soo
KS
Kim
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy* / Q000503:physiopathology; D004452:Echocardiography; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D020334:Rats, Inbred OLETF; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
D001786:Blood Glucose; D019253:Proto-Oncogene Proteins c-bcl-2; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor