Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer.
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.
Zadelaar
A Susanne M
AS
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
von der Thüsen
Jan H
JH
Boesten
Lianne S M
LS
Hoeben
Rob C
RC
Kockx
Mark M
MM
Versnel
Marjan A
MA
van Berkel
Theo J C
TJ
Havekes
Louis M
LM
Biessen
Erik A L
EA
van Vlijmen
Bart J M
BJ
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
D001057:Apolipoproteins E; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D048069:Tumor Necrosis Factors