Induction of atherosclerotic plaque rupture in apolipoprotein E-/- mice after adenovirus-mediated transfer of p53

• Published in: Circulation (New York, N.Y.) Vol. 105; no. 17; pp. 2064 - 2070
• Main Authors: VON DER THÜSEN, Jan H, VAN VLIJMEN, Bart J. M, HOEBEN, Rob C, KOCKX, Mark M, HAVEKES, Louis M, VAN BERKEL, Theo J. C, BIESSEN, Erik A. L
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 30.04.2002; American Heart Association, Inc
• Subjects: Adenoviridae - genetics; Animals; Apolipoproteins E - genetics; Apoptosis; Arteriosclerosis - etiology; Arteriosclerosis - pathology; Atherosclerosis (general aspects, experimental research); beta-Galactosidase - analysis; Biological and medical sciences; Biomarkers - analysis; Blood and lymphatic vessels; Cardiology. Vascular system; Carotid Artery Diseases - pathology; Cell Division; Genetic Vectors; Immunohistochemistry; Medical sciences; Mice; Mice, Knockout; Muscle, Smooth, Vascular - chemistry; Muscle, Smooth, Vascular - pathology; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - physiology; Pathogenesis; Rodentia; Cardiovascular disease; Genetic determinism; Genetic transfer; Vascular disease; Vertebrata; Mammalia; Mouse; Atherosclerotic plaque; Animal; Atherosclerosis; Tissue rupture; Tumor suppressor gene
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.cir.0000015502.97828.93

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. 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). 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.