title: Activated monocytes induce smooth muscle cell death: role of macrophage colony-stimulating factor and cell contact.
abstract: BACKGROUND
  Plaque disruption is the inciting event for coronary thrombosis and acute coronary syndromes. Multiple factors influence plaque rupture, including the loss of vascular smooth muscle cells (VSMCs). We hypothesized that monocytes/macrophages (MMs) activated by macrophage colony-stimulating factor (M-CSF) are responsible for VSMC death.
  
  
  RESULTS
  VSMC apoptosis was markedly increased in the presence of both M-CSF and MMs (58.8+/-3.3%) compared with VSMCs plus M-CSF without MMs (15.7+/-1.5%, P< or =0.00005), VSMCs plus MMs without M-CSF (22.7+/-3.7%, P< or =0.0001), or control VSMCs alone (13.2+/-2.1%, P< or =0.0001). MM cell contact was required for M-CSF-stimulated killing of VSMCs, and MMs displayed an M-CSF concentration-dependent killing effect. Abciximab binds Mac-1 (CD11b/CD18) on MMs. When added to VSMCs exposed to MMs and M-CSF, abciximab (7 microg/mL) significantly reduced VSMC apoptosis (19.1+/-2.2%, P< or =0.0003). Therapeutic doses of tirofiban (0.35 microg/mL) and eptifibatide (5 microg/mL), which inhibit platelet glycoprotein (GP) IIb/IIIa but not Mac-1, did not block activated MM-induced VSMC apoptosis (65.0+/-3.4% and 51.3+/-2.5%, respectively). A recombinant anti-CD-18 antibody had an effect similar to that of abciximab (16.5+/-0.4%).
  
  
  CONCLUSIONS
  These data suggest that monocytes and physiological concentrations of M-CSF trigger VSMC apoptosis. Abciximab and specific inhibitors of the Mac-1 receptor can antagonize this process.
authors.affiliation: Division of Cardiology, Department of Medicine, Emory University, Atlanta, GA, USA.
authors.forename: Puvi N
authors.initials: PN
authors.lastname: Seshiah
authors.forename: Dean J
authors.initials: DJ
authors.lastname: Kereiakes
authors.forename: Sanjay S
authors.initials: SS
authors.lastname: Vasudevan
authors.forename: Neuza
authors.initials: N
authors.lastname: Lopes
authors.forename: Baogen Y
authors.initials: BY
authors.lastname: Su
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Flavahan
authors.forename: Pascal J
authors.initials: PJ
authors.lastname: Goldschmidt-Clermont
mesh_terms: D000077284:Abciximab; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D002448:Cell Adhesion; D002478:Cells, Cultured; D018920:Coculture Techniques; D003324:Coronary Artery Disease / Q000150:complications; D003328:Coronary Thrombosis / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007375:Interleukin-1 / Q000494:pharmacology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D016177:Macrophage-1 Antigen / Q000276:immunology; D008264:Macrophages / Q000502:physiology; D008856:Microscopy, Fluorescence; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*
chemical_list: D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D007375:Interleukin-1; D016177:Macrophage-1 Antigen; D016173:Macrophage Colony-Stimulating Factor; D000077284:Abciximab