Journal
CIRCULATION
Volume 105, Issue 2, Pages 174-180Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/hc0202.102248
Keywords
apoptosis; muscle, smooth; cell adhesion molecules; plaque; inflammation
Funding
- NHLBI NIH HHS [HL-52315, HL-56091] Funding Source: Medline
- NIGMS NIH HHS [GM-53236] Funding Source: Medline
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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%, Pless than or equal to0.00005), VSMCs plus MMs without M-CSF (22.7+/-3.7%, Pless than or equal to0.0001), or control VSMCs alone (13.2+/-2.1%, Pless than or equal to0.0001). 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 less than or equal to(CD11b/CD18) on MMs. When added to VSMCs exposed to MMs and M-CSF, abciximab (7 mug/mL) significantly reduced VSMC apoptosis (19.1+/-2.2%, Pless than or equal to0.0003). Therapeutic doses of tirofiban (0.35 mug/mL) and eptifibatide (5 mug/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.
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