MCSF expression is induced in healing myocardial infarcts and may regulate monocyte and endothelial cell phenotype.
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.
Frangogiannis
Nikolaos G
NG
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
Mendoza
Leonardo H
LH
Ren
Guofeng
G
Akrivakis
Spyridon
S
Jackson
Peggy L
PL
Michael
Lloyd H
LH
Smith
C Wayne
CW
Entman
Mark L
ML
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*
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