Circulation. 2002;105:2064-2070
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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(Circulation. 2002;105:2064.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Induction of Atherosclerotic Plaque Rupture in Apolipoprotein E-/- Mice After Adenovirus-Mediated Transfer of p53
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.
Correspondence to Jan von der Thüsen, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Wassenaarseweg 72, PO Box 9503, 2300 RA Leiden, The Netherlands. 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.
Key Words: apoptosis • atherosclerosis • carotid arteries • genes • muscle
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