doi: 10.1161/hc0202.102248
(Circulation. 2002;105:174.)
© 2002 American Heart Association, Inc.
Clinical Investigation and Reports |
Activated Monocytes Induce Smooth Muscle Cell Death
Role of Macrophage Colony-Stimulating Factor and Cell Contact
From the Division of Cardiology, Department of Medicine, Emory University, Atlanta, Ga (P.S.); the Division of Cardiology, Department of Medicine, Duke University, Durham, NC (S.V., N.L., P.J.G.C.); Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, Ohio (B.Y.S, N.A.F.); and the Carl and Edyth Lindner Research Center, Cincinnati, Ohio (D.K.).
Dr Goldschmidt-Clermont receives research funding from Genentech and Centocor.Correspondence to Pascal J. Goldschmidt-Clermont, Division of Cardiology, DUMC 3845, Duke University School of Medicine, Durham, NC 27710. E-mail golds017{at}mc.duke.edu
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.
Methods and 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
0.00005), VSMCs plus MMs without M-CSF (22.7±3.7%, P0.0001), or control VSMCs alone (13.2±2.1%, P0.0001). 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 µg/mL) significantly reduced VSMC apoptosis (19.1±2.2%, P0.0003). Therapeutic doses of tirofiban (0.35 µg/mL) and eptifibatide (5 µg/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.
Key Words: apoptosis • muscle, smooth • cell adhesion molecules • plaque • inflammation
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