Journal
ATHEROSCLEROSIS
Volume 183, Issue 2, Pages 244-250Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2005.03.044
Keywords
apoptosis; atherosclerosis; carotid arteries; gene expression; vascular smooth muscle
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Objective: The death receptor Fas and Fas ligand (FasL) are present inhuman 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. Methods and results: Carotid atherogenesis was initiated in apolipoprotein E-deticient mice by placement of a perivascular silastic collar. The resulting plaques were incubated transluminally with recombinant adenovirus carrying FasL (Ad-FasL, lateral) or control P-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. (c) 2005 Published by Elsevier Ireland Ltd.
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