on April 15, 2002
Circulation. 2002
Published online before print April 15, 2002, doi: 10.1161/01.CIR.0000015502.97828.93
Published online before print April 15, 2002, doi: 10.1161/01.CIR.0000015502.97828.93
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Submitted on December 4, 2001
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., B.J.M.v.V.), Leiden University Medical Center; and TNO Prevention and Health (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. * To whom correspondence should be addressed. E-mail: thuesen{at}lacdr.leidenuniv.nl.
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 ß-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.
Revised on February 12, 2002
Accepted on February 14, 2002
Induction of Atherosclerotic Plaque Rupture in
Apolipoprotein E-/- Mice After
Adenovirus-Mediated Transfer of p53
Jan H. von der Thüsen MD*,
Key words: apoptosis • atherosclerosis • carotid arteries • genes • muscle
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