|Smith, C Wayne|
Submitted to: American Journal of Physiology - Heart and Circulatory Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/7/2003
Publication Date: 4/10/2003
Citation: FRANGOGIANNIS, N.G., MENDOZA, L.H., REN, G., AKRIVAKIS, S., JACKSON, P.L., MICHAEL, L.H., SMITH, C.W., ENTMAN, M.L. 2003. MCSF EXPRESSION IS INDUCED IN HEALING MYOCARDIAL INFARCTS AND MAY REGULATE MONOCYTE AND ENDOTHELIAL CELL PHENOTYPE. AMERICAN JOURNAL OF PHYSIOLOGY: HEART AND CIRCULATORY PHYSIOLOGY. 285:H483-H492. Interpretive Summary: Atherosclerosis of coronary vessels often leads to occlusion of the vessel with damage to the cardiac tissue. We have been studying the role the innate immune response may have in causing tissue injury as well as promoting healing. This paper deals with the hormones (called cytokines) that are important in attracting and activating white blood cells in the healing process. Here we demonstrate that monocyte colony stimulating factor (M-CSF) is produced by the heart, a cytokine that is known to promote innate immune contributions to healing.
Technical Abstract: 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.