MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype

1 Section of Cardiovascular Sciences, Department of Medicine, the Methodist Hospital and the DeBakey Heart Center, and 2 Section of Leukocyte Biology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030 Submitted 2 December 2002 ; accepted in final form 7 April 2003 Myocardial infarction is associated with the rapid induction of mononuclear cell chemoattractants that promote monocyte infiltration into the injured area. Monocyte-to-macrophage differentiation and macrophage proliferation allow a long survival of monocytic cells, critical for effective healing of the infarct. In a canine infarction-reperfusion model, newly recruited myeloid leukocytes were markedly augmented during early reperfusion (5–72 h). By 7 days, the number of newly recruited myeloid cells was reduced, and the majority of the inflammatory cells remaining in the infarct were mature macrophages. Macrophage colony-stimulating factor (MCSF) is known to facilitate monocyte survival, monocyte-to-macrophage conversion, and macrophage proliferation. We demonstrated marked induction of MCSF mRNA in ischemic segments persisting for at least 5 days after reperfusion. MCSF expression was predominantly localized to mature macrophages infiltrating the infarcted myocardium; the expression of the MCSF receptor, c-Fms, a protein with tyrosine kinase activity, was found in these macrophages but was also observed in a subset of microvessels within the infarct. Many infarct macrophages expressed proliferating cell nuclear antigen, a marker of proliferative activity. In vitro MCSF induced monocyte chemoattractant protein-1 synthesis in canine venous endothelial cells. MCSF-induced endothelial monocyte chemoattractant protein-1 upregulation was inhibited by herbimycin A, a tyrosine kinase inhibitor, and by LY-294002, a phosphatidylinositol 3'-kinase inhibitor. We suggest that upregulation of MCSF in the infarcted myocardium may have an active role in healing not only through its effects on cells of monocyte/macrophage lineage, but also by regulating endothelial cell chemokine expression. inflammation; reperfusion; chemokine; growth factors; macrophage colony-stimulating factor Address for reprint requests and other correspondence: N. G. Frangogiannis, Section of Cardiovascular Sciences, One Baylor Plaza, M/S F-602, Houston, TX 77030 (E-mail: ngf{at}bcm.tmc.edu ).