Role of endogenous Fas (CD95/Apo-1) ligand in balloon-induced apoptosis, inflammation, and neointima formation.
BACKGROUND
Fas (CD95/Apo-1) ligand (FasL)-induced apoptosis in Fas-bearing cells is critically involved in modulating immune reactions and tissue repair. Apoptosis has also been described after mechanical vascular injury such as percutaneous coronary intervention. However, the relevance of cell death in this context of vascular repair remains unknown.


RESULTS
To determine whether FasL-induced apoptosis is causally related to neointimal lesion formation, we subjected FasL-deficient (generalized lymphoproliferative disorder [gld], C57BL/6J) and corresponding wild-type (WT) mice to carotid balloon distension injury, which induces marked endothelial denudation and medial cell death. FasL expression in WT mice was induced in injured vessels compared with untreated arteries (P<0.05; n=5). Conversely, absence of functional FasL in gld mice decreased medial and intimal apoptosis (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling [TUNEL] index) at 1 hour and 7 days after balloon injury (P<0.05; n=6). In addition, peritoneal macrophages isolated from gld mice showed no apoptosis and enhanced migration (P<0.05; n=4). In parallel, we observed increased balloon-induced macrophage infiltrations (anti-CD68) in injured arteries of FasL-deficient animals (P<0.05; n=6). Together with enhanced proliferation (bromodeoxyuridine index; P<0.05), these events resulted in a further increase in medial and neointimal cells (P<0.01; n=8) with thickened neointima in gld mice (intima/media ratio, x3.8 of WT; P<0.01).


CONCLUSIONS
Our data identify proapoptotic and antiinflammatory effects of endogenous FasL as important factors in the process of neointimal lesion formation after balloon injury. Moreover, they suggest that activation of FasL may decrease neointimal thickening after percutaneous coronary intervention.
Matter
Christian M
CM
Cardiovascular Research, Institute of Physiology, University of Zurich, Cardiovascular Center, Zurich, Switzerland. cmatter@physiol.unizh.ch
Chadjichristos
Christos E
CE
Meier
Patricia
P
von Lukowicz
Tobias
T
Lohmann
Christine
C
Schuler
Pia K
PK
Zhang
Dongming
D
Odermatt
Bernhard
B
Hofmann
Eugen
E
Brunner
Thomas
T
Kwak
Brenda R
BR
Lüscher
Thomas F
TF
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism*; D017209:Apoptosis; D020212:Carotid Artery Injuries / Q000209:etiology / Q000473:pathology*; D002404:Catheterization / Q000009:adverse effects*; D002465:Cell Movement; D049109:Cell Proliferation; D053222:Fas Ligand Protein; D008232:Lymphoproliferative Disorders / Q000473:pathology / Q000503:physiopathology*; D008264:Macrophages / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000473:pathology; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000378:metabolism*; D017539:Tunica Intima / Q000473:pathology*; D017540:Tunica Media / Q000473:pathology
D000893:Anti-Inflammatory Agents; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors