Published online before print December 13, 2001, doi: 10.1161/hh0202.103715
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© 2002 American Heart Association, Inc.
Integrative Physiology |
Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice
From the Institute for Pathophysiology (U.M., H.D., Y.H.), University of Innsbruck and Institute for Biomedical Aging Research (M.M, C.L, F.W., Q.X.), Austrian Academy of Sciences, Innsbruck, Austria; and the Department of Cardiological Sciences (F.W., Q.X.), St George’s Hospital Medical School, London, UK. Present address for U.M., M.M, and Y.H. is the Department of Cardiological Sciences, St George’s Hospital Medical School, London, UK.
Correspondence to Prof Qingbo Xu, Department of Cardiological Sciences, St George’s Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK. E-mail q.xu{at}sghms.ac.uk
The transcription factor p53 is essentially involved in regulation of cell death and proliferation. Recently, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of p53 in the development of vein graft arteriosclerosis in p53-/- mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in p53-/- mice was increased 2-fold compared with that of wild-type controls. Cell component analysis revealed that neointimal lesions in p53-/- mice consisted mainly of 
-actin positive smooth muscle cells (SMCs), whereas the majority of cells in wild-type mice were MAC-1 (CD11b/18)-positive at 4 weeks. Importantly, SMC apoptosis as determined by TUNEL assay was significantly reduced in p53-/- vein grafts. TUNEL positive cells in wild-type vein grafts markedly increased from 0.5% to 6.4% of total cells 4 weeks postoperatively, but remained virtually unchanged in p53-/- grafts (0.8%). Immunofluorescence analysis revealed that increased p53 expression in neointimal SMCs of wild-type, but not p53-/-, mice coincided with oxidative DNA damage in vein grafts. Interestingly, SMCs of p53-/- mice showed increased apoptosis in response to TNF and decreased apoptosis in response to sodium nitroprusside. Additionally, p53-deficient SMCs showed a higher rate of proliferation and migration and expressed higher levels of matrix metalloproteinases. Thus, p53 deficiency accelerates neointima formation by facilitating SMC proliferation as well as abrogating cell apoptosis.
Key Words: animal models • vein grafts • apoptosis • p53 • neointima hyperplasia
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