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Originally published online as doi:10.2353/ajpath.2007.061191 on August 23, 2007

Published online before print August 23, 2007
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(American Journal of Pathology. 2007;171:1093-1103.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.061191

Macrophage Colony-Stimulating Factor Improves Cardiac Function after Ischemic Injury by Inducing Vascular Endothelial Growth Factor Production and Survival of Cardiomyocytes

Tatsuma Okazaki*, Satoru Ebihara*, Masanori Asada*, Shinsuke Yamanda*, Yoshifumi Saijo{dagger}, Yasuyuki Shiraishi{dagger}, Takae Ebihara*, Kaijun Niu*, He Mei*, Hiroyuki Arai* and Tomoyuki Yambe{dagger}

From the Department of Geriatrics and Gerontology,* Tohoku University School of Medicine, Sendai; and the Department of Medical Engineering and Cardiology,{dagger} Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan

Macrophage colony-stimulating factor (M-CSF), known as a hematopoietic growth factor, induces vascular endothelial growth factor (VEGF) production from skeletal muscles. However, the effects of M-CSF on cardiomyocytes have not been reported. Here, we show M-CSF increases VEGF production from cardiomyocytes, protects cardiomyocytes and myotubes from cell death, and improves cardiac function after ischemic injury. In mice, M-CSF increased VEGF production in hearts and in freshly isolated cardiomyocytes, which showed M-CSF receptor expression. In rat cell line H9c2 cardiomyocytes and myotubes, M-CSF induced VEGF production via the Akt signaling pathway, and M-CSF pretreatment protected these cells from H2O2-induced cell death. M-CSF activated Akt and extracellular signal-regulated kinase signaling pathways and up-regulated downstream anti-apoptotic Bcl-xL expression in these cells. Using goats as a large animal model of myocardial infarction, we found that M-CSF treatment after the onset of myocardial infarction by permanent coronary artery ligation promoted angiogenesis in ischemic hearts but did not reduce the infarct area. M-CSF pretreatment of the goat myocardial infarction model by coronary artery occlusion-reperfusion improved cardiac function, as assessed by hemodynamic parameters and echocardiography. These results suggest M-CSF might be a novel therapeutic agent for ischemic heart disease.




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