Published online before print August 23, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061191

Accepted for publication June 27, 2007.

Article

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, Yasuyuki Shiraishi, Takae Ebihara^*, Kaijun Niu^*, He Mei^*, Hiroyuki Arai^*, and Tomoyuki Yambe

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

^@ To whom correspondence should be addressed. E-mail: s_ebihara{at}geriat.med.tohoku.ac.jp.

	Abstract

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.