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.
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.
authors.affiliation: Unit of Cardiovascular Medicine, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Scott
authors.forename: Michael
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: Sassan
authors.initials: S
authors.lastname: Hafizi
authors.forename: Leonard M
authors.initials: LM
authors.lastname: Shapiro
authors.forename: Martin R
authors.initials: MR
authors.lastname: Bennett
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000378:metabolism* / Q000473:pathology; D003331:Coronary Vessels / Q000473:pathology; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000187:drug effects / Q000528:radiation effects; D022761:Gene Transfer, Horizontal; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D006083:Graft Occlusion, Vascular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D018715:Microscopy, Video; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D027383:Papillomaviridae / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D014466:Ultraviolet Rays; D010948:Viral Plaque Assay
chemical_list: D056741:Cyclin D; D016213:Cyclins; D019384:Nucleic Acid Synthesis Inhibitors; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D005047:Etoposide