title: Apoptosis of vascular smooth muscle cells is induced by Fas ligand derived from monocytes/macrophage.
abstract: 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.
authors.affiliation: Division of Cardiology, Department of Medicine, Wakayama Medical College, 811-1, Kimiidera, Wakayama City, Wakayama 641-8510, Japan. t-imani@wakayama.hosp.go.jp
authors.forename: Toshio
authors.initials: T
authors.lastname: Imanishi
authors.forename: David K
authors.initials: DK
authors.lastname: Han
authors.forename: Leonard
authors.initials: L
authors.lastname: Hofstra
authors.forename: Takuzo
authors.initials: T
authors.lastname: Hano
authors.forename: Ichiro
authors.initials: I
authors.lastname: Nishio
authors.forename: W Conrad
authors.initials: WC
authors.lastname: Liles
authors.forename: Alan M
authors.initials: AM
authors.lastname: Gown
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Schwartz
authors.forename: David K M
authors.initials: DK
authors.lastname: Han
authors.forename: Alan M
authors.initials: AM
authors.lastname: Gorden
mesh_terms: 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
chemical_list: D000936:Antigen-Antibody Complex; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D002857:Chromium; D015054:Zymosan