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Atherosclerosis. 2005 Dec;183(2):244-50. Epub 2005 May 31.

Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer.

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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.



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.


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.


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.

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