Published online before print January 31, 2002, doi: 10.1161/hh0402.105900
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© 2002 American Heart Association, Inc.
Molecular Medicine |
Human Vascular Smooth Muscle Cells From Restenosis or In-Stent Stenosis Sites Demonstrate Enhanced Responses to p53
Implications for Brachytherapy and Drug Treatment for Restenosis
From the Unit of Cardiovascular Medicine (S.S., M.O.’S., M.R.B.), Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Cambridge, UK; Heart Sciences Centre (S.H.), Harefield Hospital, Middlesex, UK; Cardiac Unit (L.M.S., M.R.B.), Papworth Hospital, Cambridge, UK.
Correspondence to Professor M.R. Bennett, University of Cambridge, Division of Cardiovascular Medicine, Addenbrooke’s Centre for Clinical Investigation, Addenbrooke’s Hospital, Box 110, Hills Road, Cambridge, CB2 2QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk
The p53 tumor suppressor gene regulates growth arrest and apoptosis after DNA damage. Recent studies suggest that p53 is inactive in vascular smooth muscle cells (VSMCs) in human angioplasty restenosis, promoting VSMC accumulation and vessel stenosis. In contrast, the success of irradiation (brachytherapy) for in-stent restenosis argues that DNA-damage p53 responses are intact. We examined p53 expression and function in human VSMCs from normal vessels (n-VSMCs) and angioplasty/in-stent restenosis sites (r-VSMCs). p53 expression was uniformly low in all VSMCs and was induced by DNA damage. However, p53 induced profoundly different biological effects in r-VSMCs versus n-VSMCs, causing growth arrest and apoptosis in r-VSMCs only. In addition, dominant-negative p53 promoted cell proliferation and apoptosis in r-VSMCs but not n-VSMCs. Cytotoxic drug– or irradiation-induced growth arrest and apoptosis in both cell types was mediated only partly by p53. In contrast, cyclin D degradation in response to DNA damage, a critical early mediator of growth arrest, was impaired in r-VSMCs, an effect that required p53. We conclude that p53 expression and function are normal or increased in r-VSMCs and may underlie the success of brachytherapy. We also identify a restenosis VSMC-specific defect in cyclin D degradation induced by DNA damage.
Key Words: atherosclerosis • apoptosis • restenosis • intravascular stenting • brachytherapy
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