title: 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.
  
  
  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 beta-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.
authors: Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Leiden, The Netherlands. thuesen@lacdr.leidenuniv.nl
authors: Jan H
authors: JH
authors: von der Thüsen
authors: Bart J M
authors: BJ
authors: van Vlijmen
authors: Rob C
authors: RC
authors: Hoeben
authors: Mark M
authors: MM
authors: Kockx
authors: Louis M
authors: LM
authors: Havekes
authors: Theo J C
authors: TJ
authors: van Berkel
authors: Erik A L
authors: EA
authors: Biessen
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D017209:Apoptosis; D001161:Arteriosclerosis / Q000209:etiology / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D002340:Carotid Artery Diseases / Q000473:pathology; D002455:Cell Division; D005822:Genetic Vectors; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000473:pathology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000502:physiology*; D001616:beta-Galactosidase / Q000032:analysis
chemical_list: D001057:Apolipoproteins E; D015415:Biomarkers; D016159:Tumor Suppressor Protein p53; D001616:beta-Galactosidase