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(Circulation. 2006;113:1879-1887.)
© 2006 American Heart Association, Inc.

Vascular Medicine

Role of Endogenous Fas (CD95/Apo-1) Ligand in Balloon-Induced Apoptosis, Inflammation, and Neointima Formation

Christian M. Matter, MD; Christos E. Chadjichristos, PhD; Patricia Meier; Tobias von Lukowicz, MD; Christine Lohmann; Pia K. Schuler, MD; Dongming Zhang, MD; Bernhard Odermatt, MD; Eugen Hofmann; Thomas Brunner, PhD; Brenda R. Kwak, PhD; Thomas F. Lüscher, MD

From Cardiovascular Research, Institute of Physiology, University of Zurich, and Cardiovascular Center, University Hospital Zurich, Zurich (C.M.M., P.M., T.v.L., C.L., P.K.S., D.Z., T.F.L.); Center for Integrative Human Physiology, University of Zurich, Zurich (C.M.M., P.M., T.v.L., C.L., T.F.L.); Division of Cardiology, University Hospital Geneva, Geneva (C.E.C., B.R.K.); Institute of Clinical Pathology, University Hospital Zurich, Zurich (B.O.); Schneider Europe, Bulach (E.H.); and Division of Immunopathology, Institute of Pathology, University of Bern, Bern (T.B.), Switzerland.

Correspondence to Christian M. Matter, MD, Department of Cardiovascular Research, Institute of Physiology, Zurich University, and Cardiovascular Center, University Hospital Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. E-mail cmatter{at}physiol.unizh.ch

Received May 6, 2005; de novo received January 2, 2006; accepted February 14, 2006.

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.

Methods and 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.

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