Cited by 203Atherosclerosis and Cardiovascular DiseasesCerebrovascular and Carotid Artery DiseasesCoronary Interventions and Diagnostics

Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E −/− Mice After Adenovirus-Mediated Transfer of p53

von der Thüsen, Jan H., van Vlijmen, Bart J.M., Hoeben, Rob C., Kockx, Mark M., Havekes, L.M., van Berkel, Theo J.C., Biessen, Erik A.L.·2002·Circulation

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.

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Crossref · 10.1161/01.cir.0000015502.97828.93

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  • Early work with adenoviral p53 expression in plaques led to VSMC apoptosis and cap thinning.

    “Early work with adenoviral p53 expression in plaques led to VSMC apoptosis and cap thinning 182 .”

    From Vascular smooth muscle cells in atherosclerosis (2019) · cites this paper as [182]

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Authors
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.
Affiliations
  • From the Division of Biopharmaceutics (J.H.v.d.T., T.J.C.v.B., E.A.L.B.), Leiden/Amsterdam Center for Drug Research; Molecular Virology Group, Department of Molecular Cell Biology (R.C.H.) and Department of Cardiology (J.H.v.d.T.), Leiden University Medical Center; and TNO-PG (B.J.M.v.V., L.M.H.), Leiden, the Netherlands; and Department of Pathology (M.M.K.), Middelheim Academic Hospital, Antwerp, Belgium.
  • Leiden University (NL)
Venue
Circulation
Published
2002-04-30
Volume
105
Issue
17
Pages
2064-2070
ISSN
  • 0009-7322 (ISSN-L)
  • 1524-4539
OpenAlex
W2122574397
Cited by
203
References
32
Citations by year
2026: 2 · 2025: 3 · 2024: 2 · 2023: 1 · 2022: 3 · 2021: 6 · 2020: 3 · 2019: 6 · 2018: 5 · 2017: 5 · 2016: 4 · 2015: 7 · 2014: 8 · 2013: 10 · 2012: 8
FWCI
5.80
Type
journal article
Language
en
Open access
closed
Locations
  • Circulation (publishedVersion)
  • PubMed (publishedVersion)
  • TNO Repository (submittedVersion)
  • Repository hosted by TU Delft Library (TU Delft) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
Funders
Koninklijke Nederlandse Akademie van Wetenschappen
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
  • Health Sciences › Medicine › Surgery › Coronary Interventions and Diagnostics
Keywords
atherosclerotic plaque rupture, p53, plaque destabilization, plaque remodeling, smooth muscle cell apoptosis, ApoE-deficient mice, adenoviral gene transfer, phenylephrine, plaque vulnerability
MeSH terms
Adenoviridae, Animals, Apolipoproteins E, Arteriosclerosis, beta-Galactosidase, Carotid Artery Diseases, Cell Division, Genetic Vectors, Immunohistochemistry, Muscle, Smooth, Vascular, Transfection, Biomarkers, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Mice

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