Published Online
on April 10, 2006

A more recent version of this article appeared on April 18, 2006

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Submitted on May 6, 2005
Revised on January 2, 2006
Accepted on February 14, 2006

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, and 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.

^* To whom correspondence should be addressed. E-mail: cmatter{at}physiol.unizh.ch.

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.

Key words: apoptosis • balloon • inflammation • restenosis

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