Advanced

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

Scott, Stephen; O'Sullivan, Michael; Hafizi, Sassan LU ; Shapiro, Leonard M and Bennett, Martin R (2002) In Circulation research 90(4). p.398-404
Abstract
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,... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
publishing date
type
Contribution to journal
publication status
published
subject
in
Circulation research
volume
90
issue
4
pages
398 - 404
publisher
American Heart Association
external identifiers
  • pmid:11884368
  • scopus:0037040853
ISSN
1524-4571
DOI
10.1161/hh0402.105900
language
English
LU publication?
no
id
53060b89-d2f8-42c2-b0c3-7694dbe77270 (old id 1124209)
date added to LUP
2008-05-30 15:26:51
date last changed
2017-07-02 04:17:21
@article{53060b89-d2f8-42c2-b0c3-7694dbe77270,
  abstract     = {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.},
  author       = {Scott, Stephen and O'Sullivan, Michael and Hafizi, Sassan and Shapiro, Leonard M and Bennett, Martin R},
  issn         = {1524-4571},
  language     = {eng},
  number       = {4},
  pages        = {398--404},
  publisher    = {American Heart Association},
  series       = {Circulation research},
  title        = {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},
  url          = {http://dx.doi.org/10.1161/hh0402.105900},
  volume       = {90},
  year         = {2002},
}