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Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E −/− Mice After Adenovirus-Mediated Transfer of 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.
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“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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Cell cycle and apoptosis genes in atherosclerosis
Boesten, L. S. M. (2006) · Leiden Repository (Leiden University)
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Atherosclerotic Plaque Disruption Induced by Stress and Lipopolysaccharide in
Ni, M., Wang, Y., Zhang, M., Zhang, P., Ding, S. F., Liu, C. X., Liu, X. L., Zhao, Y. X., & Zhang, Y. (2009)
Apoptosis and Plaque Vulnerability
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PPAP2B EXPRESSION LIMITS LESION FORMATION IN MURINE MODELS OF ATHEROSCLEROSIS
Mueller, P. A. (2016) · UKnowledge (University of Kentucky) · doi:10.13023/etd.2016.299
Role of Cathepsin G in Atherosclerosis
Rafatian, N. (2013) · uO Research (University of Ottawa) · doi:10.20381/ruor-6368
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Metadata
- 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 › Cardiology and Cardiovascular Medicine › Cerebrovascular and Carotid Artery Diseases
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › 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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