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Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53

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Author: Thüsen, J.H. von der · Vlijmen, B.J.M. van · Hoeben, R.C. · Kockx, M.M. · Havekes, L.M. · Berkel, T.J.C. van · Biessen, E.A.L.
Type:article
Date:2002
Source:Circulation, 17, 105, 2064-2070
Identifier: 236530
doi: doi:/10.1161/01.CIR.0000015502.97828.93
Keywords: 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

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