Increased vulnerability of pre-existing atherosclerosis in ApoE-deficient mice following adenovirus-mediated Fas ligand gene transfer
article
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. Methods and 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 β-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. Chemicals / CAS: Apolipoproteins E; Fas Ligand Protein; Fasl protein, mouse; FASLG protein, human; Membrane Glycoproteins; Tumor Necrosis Factors
Topics
Biomedical ResearchApoptosisAtherosclerosisCarotid arteriesGene expressionVascular smooth muscleadenovirus vectorapolipoprotein Ebeta galactosidaseFAS ligandanimal cellanimal experimentanimal modelanimal tissueatherosclerotic plaquecarotid arterycontrolled studygene expressiongene transfermalemousenonhumanphenotypeprotein expressionsilastic tubesmooth muscleAdenoviridaeAnimalsApolipoproteins EApoptosisAtherosclerosisCarotid ArteriesCarotid Artery DiseasesDisease Models, AnimalDisease ProgressionFas Ligand ProteinFollow-Up StudiesGene TherapyGenetic VectorsMembrane GlycoproteinsMiceTransfectionTumor Necrosis Factors
TNO Identifier
238885
ISSN
00219150
Source
Atherosclerosis, 183(2), pp. 244-250.
Pages
244-250
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