Title
Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53
Author
von der Thüsen, J.H.
van Vlijmen, B.J.M.
Hoeben, R.C.
Kockx, M.M.
Havekes, L.M.
van Berkel, T.J.C.
Biessen, E.A.L.
Publication year
2002
Abstract
Background - The presence of the tumor-suppressor gene p53 in advanced atherosclerotic plaques and the sensitivity to p53-induced cell death of smooth muscle cells isolated from these plaques have fueled speculation about the role of p53 in lesion destabilization and plaque rupture. In this study, we describe a strategy to promote (thrombotic) rupture of preexisting atherosclerotic lesions using p53-induced lesion remodeling. Methods and Results - Carotid atherogenesis was initiated in apolipoprotein E knockout mice by placement of a perivascular silastic collar. The resulting plaques were incubated transluminally with recombinant adenovirus carrying either a p53 or β-galactosidase (lacZ) transgene. p53 transfection was restricted to the smooth muscle cell-rich cap of the plaque and led to an increase in cap cell apoptosis 1 day after transfer. p53 overexpression resulted in a marked decrease in the cellular and extracellular content of the cap, reflected by a markedly reduced cap/intima ratio (0.21±0.04 versus 0.46±0.03, P<0.001). The latter is a characteristic feature of plaque vulnerability to rupture, and whereas spontaneous rupture of p53-treated lesions was rare, it was found in 40% of cases after treatment with the vasopressor compound phenylephrine (P=0.003). Conclusions - We have demonstrated a potential role of p53-induced remodeling in atherosclerotic plaque destabilization. Being the first example of inducible rupture at a predefined location, this model offers a unique opportunity to delineate the processes that precede rupture and to evaluate plaque- stabilizing therapies. Chemicals/CAS: Apolipoproteins E; beta-Galactosidase, EC 3.2.1.23; Biological Markers; Tumor Suppressor Protein p53
Subject
Health
Carotid arteries
Genes
Muscle
Adenovirus vector
Apolipoprotein E
Beta galactosidase
Phenylephrine
Protein p53
Animal experiment
Animal model
Atherogenesis
Atherosclerotic plaque
Carotid artery
Cell death
Controlled study
Gene overexpression
Genetic transfection
Knockout mouse
Mouse
Nonhuman
Rupture
Smooth muscle fiber
Thrombosis
Transgene
Tumor suppressor gene
Adenoviridae
Animals
Apolipoproteins E
Apoptosis
Arteriosclerosis
beta-Galactosidase
Biological Markers
Carotid Artery Diseases
Cell Division
Genetic Vectors
Immunohistochemistry
Mice
Mice, Knockout
Muscle, Smooth, Vascular
Transfection
Tumor Suppressor Protein p53
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DOI
https://doi.org/10.1161/01.cir.0000015502.97828.93
TNO identifier
236530
ISSN
0009-7322
Source
Circulation, 105 (17), 2064-2070
Document type
article