Apoptosis of vascular smooth muscle cells is induced by Fas ligand derived from monocytes/macrophage.
Fas and its ligand (FasL), are a receptor-ligand pair identified as promoting cell death in several tissues. Apoptosis of vascular smooth muscle cells (VSMCs) in human atherosclerotic plaque may contribute to weakening of the fibrous cap, ultimately resulting in plaque rupture. We investigated the ability of monocytes to induce apoptosis of cultured VSMCs through Fas/FasL pathway. In addition, we examined the association of FasL with apoptosis in human coronary plaques. Both activated monocytes and the supernatant obtained from activated monocytes were able to kill cultured VSMCs. The apoptotic response of VSMCs was almost completely blocked by the caspase inhibitor z-VAD-fmk and was partially blocked by incubation with antagonistic anti-Fas IgG1 which suggests that Fas/FasL system was involved in the induction of cell death. An approximate 30 kDa protein, which represents a cleaved, soluble form of FasL, was identified in culture medium from activated monocytes, but not in culture medium from control, unactivated monocytes. Immunohistochemical analysis of human atherosclerotic coronary lesions showed that FasL is expressed by macrophages, and microvessels in the adventitia as well as in the plaque. Finally, double-staining with terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and FasL antibody showed that FasL enriched lesions always included a number of TUNEL-positive cells. These data suggest that Fas/FasL pathway can be employed by monocytes/macrophages to induce VSMC apoptosis in the atherosclerotic lesions.
Imanishi
Toshio
T
Division of Cardiology, Department of Medicine, Wakayama Medical College, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama.hosp.go.jp
Han
David K
DK
Hofstra
Leonard
L
Hano
Takuzo
T
Nishio
Ichiro
I
Liles
W Conrad
WC
Gown
Alan M
AM
Schwartz
Stephen M
SM
Han
David K M
DK
Gorden
Alan M
AM
D000936:Antigen-Antibody Complex / Q000494:pharmacology; D017209:Apoptosis; D001161:Arteriosclerosis / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002478:Cells, Cultured; D002857:Chromium / Q000378:metabolism; D053222:Fas Ligand Protein; D006801:Humans; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology*; D015054:Zymosan / Q000494:pharmacology
D000936:Antigen-Antibody Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D002857:Chromium; D015054:Zymosan