title: Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer.
abstract: OBJECTIVE
  The death receptor Fas and Fas ligand (FasL) are present in human advanced atherosclerotic plaques. The activation of the Fas/FasL pathway of apoptosis has been implicated in plaque vulnerability. In the present study, we investigated whether overexpression of FasL in pre-existing atherosclerotic lesions can induce lesion remodelling and rupture-related events.
  
  
  RESULTS
  Carotid atherogenesis was initiated in apolipoprotein E-deficient mice by placement of a perivascular silastic collar. The resulting plaques were incubated transluminally with recombinant adenovirus carrying FasL (Ad-FasL, lateral) or control beta-galactosidase (Ad-LacZ, contralateral). Transfection was restricted to the smooth muscle cell-rich cap of the plaque, and FasL expression led to a three-fold increase in apoptosis in the cap one day after gene transfer. Three days after gene transfer, FasL expression led to a 38% reduction in the number of cap cells. Two weeks after Ad-FasL transfer, non-thrombotic rupture, intra-plaque haemorrhage, buried caps and iron deposits were observed in 6 out of 17 Ad-FasL-treated carotid arteries versus 0 out of 17 controls (P=0.009), indicative of enhanced plaque vulnerability.
  
  
  CONCLUSIONS
  These data demonstrate that advanced murine plaques are sensitive to Fas/FasL-induced apoptosis, which may indicate that stimulation of this pathway could result in plaque remodelling towards a more vulnerable phenotype.
authors.affiliation: Department of Cardiology, Leiden University Medical Center c/o TNO Prevention and Health, Gaubius Laboratory, Zernikedreef 9, P.O. Box 2215, 2301 CE Leiden, The Netherlands. asm.zalelaar@pg.tno.nl
authors.forename: A Susanne M
authors.initials: AS
authors.lastname: Zadelaar
authors.forename: Jan H
authors.initials: JH
authors.lastname: von der Thüsen
authors.forename: Lianne S M
authors.initials: LS
authors.lastname: Boesten
authors.forename: Rob C
authors.initials: RC
authors.lastname: Hoeben
authors.forename: Mark M
authors.initials: MM
authors.lastname: Kockx
authors.forename: Marjan A
authors.initials: MA
authors.lastname: Versnel
authors.forename: Theo J C
authors.initials: TJ
authors.lastname: van Berkel
authors.forename: Louis M
authors.initials: LM
authors.lastname: Havekes
authors.forename: Erik A L
authors.initials: EA
authors.lastname: Biessen
authors.forename: Bart J M
authors.initials: BJ
authors.lastname: van Vlijmen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D017209:Apoptosis; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000473:pathology; D002339:Carotid Arteries / Q000473:pathology; D002340:Carotid Artery Diseases / Q000097:blood / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D053222:Fas Ligand Protein; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000009:adverse effects*; D005822:Genetic Vectors; D008297:Male; D008562:Membrane Glycoproteins / Q000009:adverse effects* / Q000235:genetics; D051379:Mice; D014162:Transfection; D048069:Tumor Necrosis Factors / Q000009:adverse effects* / Q000235:genetics
chemical_list: D001057:Apolipoproteins E; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors