TY - JOUR
T1 - Activated monocytes induce smooth muscle cell death role of macrophage colony-stimulating factor and cell contact
AU - Seshiah, Puvi N.
AU - Kereiakes, Dean J.
AU - Vasudevan, Sanjay S.
AU - Lopes, Neuza
AU - Su, Baogen Y.
AU - Flavahan, Nicholas A.
AU - Goldschmidt-Clermont, Pascal J.
PY - 2002/1/15
Y1 - 2002/1/15
N2 - 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%, P≤0.0001), or control VSMCs alone (13.2±2.1%, P≤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 μg/mL) significantly reduced VSMC apoptosis (19.1±2.2%, P≤0.0003). 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.
AB - 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%, P≤0.0001), or control VSMCs alone (13.2±2.1%, P≤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 μg/mL) significantly reduced VSMC apoptosis (19.1±2.2%, P≤0.0003). 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.
KW - Apoptosis
KW - Cell adhesion molecules
KW - Inflammation
KW - Muscle, smooth
KW - Plaque
UR - http://www.scopus.com/inward/record.url?scp=0037080526&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037080526&partnerID=8YFLogxK
U2 - 10.1161/hc0202.102248
DO - 10.1161/hc0202.102248
M3 - Article
C2 - 11790697
AN - SCOPUS:0037080526
SN - 0009-7322
VL - 105
SP - 174
EP - 180
JO - Circulation
JF - Circulation
IS - 2
ER -