title: MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype.
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.
authors.affiliation: Section of Cardiovascular Sciences, Department of Medicine, Methodist Hospital and DeBakey Heart Center, One Baylor Plaza, M/S F-602, Houston, TX 77030, USA. ngf@bcm.tmc.edu
authors.forename: Nikolaos G
authors.initials: NG
authors.lastname: Frangogiannis
authors.forename: Leonardo H
authors.initials: LH
authors.lastname: Mendoza
authors.forename: Guofeng
authors.initials: G
authors.lastname: Ren
authors.forename: Spyridon
authors.initials: S
authors.lastname: Akrivakis
authors.forename: Peggy L
authors.initials: PL
authors.lastname: Jackson
authors.forename: Lloyd H
authors.initials: LH
authors.lastname: Michael
authors.forename: C Wayne
authors.initials: CW
authors.lastname: Smith
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D018932:Chemokine CCL2 / Q000235:genetics; D003326:Coronary Circulation; D004285:Dogs; D004730:Endothelium, Vascular / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007601:Jugular Veins; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology; D008297:Male; D009000:Monocytes / Q000166:cytology*; D009203:Myocardial Infarction / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D015428:Myocardial Reperfusion Injury / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics; D014945:Wound Healing / Q000276:immunology*
chemical_list: D018932:Chemokine CCL2; D012333:RNA, Messenger; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor