PRECLINICAL STUDY
Cardioprotective Effects of Granulocyte Colony-Stimulating Factor in Swine With Chronic Myocardial Ischemia
Hiroshi Hasegawa, MD, PhD,
Hiroyuki Takano, MD, PhD,
Koji Iwanaga, DVM,
Masashi Ohtsuka, MD, PhD,
Yingjie Qin, MD,
Yuriko Niitsuma, MD,
Kazutaka Ueda, MD,
Tomohiko Toyoda, MD, PhD,
Hiroyuki Tadokoro, MD and
Issei Komuro, MD, PhD*
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
Manuscript received July 14, 2005;
revised manuscript received September 13, 2005,
accepted September 26, 2005.
* Reprint requests and correspondence: Dr. Issei Komuro, Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan. (Email: komuro-tky{at}umin.ac.jp).
OBJECTIVES: The aim of this study was to investigate the effect of granulocyte colony-stimulating factor (G-CSF) on chronic myocardial ischemia in swine.
BACKGROUND: We recently have reported that G-CSF prevents cardiac remodeling and dysfunction after acute myocardial infarction in mice and swine. It remains unclear whether G-CSF has beneficial effects on chronic myocardial ischemia.
METHODS: An ameroid constrictor was placed on left circumflex coronary artery of swine. The presence of myocardial ischemia was verified at four weeks after the operation, and the animals were randomly assigned into the following two groups: 1) administration of vehicle (control group, n = 10), and 2) administration of G-CSF (10 µg/kg/day) for seven days (G-CSF group, n = 10).
RESULTS: Echocardiographic examination revealed that the G-CSF treatment prevented left ventricular dilation and dysfunction at eight weeks after the operation. Stress echocardiography revealed that G-CSF ameliorated the regional contractility of chronic myocardial ischemia. Morphological analysis revealed that the extent of myocardial fibrosis of the ischemic region was less in the G-CSF group than in control group. There were more vessels and less apoptotic cells at the ischemic region of the heart of the G-CSF group than control group. Moreover, Akt1 was more strongly activated in the heart of the G-CSF group than control group.
CONCLUSIONS: These findings suggest that G-CSF improves cardiac function of chronic myocardial ischemia through decreases in fibrosis and apoptotic death and an increase in vascular density in the ischemic region.
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Abbreviations and Acronyms
| | DOB = dobutamine | | ECs = endothelial cells | | EPC = endothelial progenitor cell | | FAC = fractional area change | | G-CSF = granulocyte colony-stimulating factor | | LCX = left circumflex coronary artery | | LV = left ventricle | | LVEDA = left ventricular end-diastolic area | | LVEDP = left ventricular end-diastolic pressure | | LVESA = left ventricular end-systolic area | | MI = myocardial infarction | | TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-digoxigenin nick end labeling | | VEGF = vascular endothelial growth factor | | vWF = von Willebrand factor |
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