© 1997 American Heart Association, Inc.
Articles |
Increased Sensitivity of Human Vascular Smooth Muscle Cells From Atherosclerotic Plaques to p53-Mediated Apoptosis
From the Unit of Cardiovascular Medicine (M.R.B., P.L.W.), University of Cambridge (UK) Clinical School of Medicine, Department of Medicine, Addenbrooke's Hospital, and the Biochemistry of the Cell Nucleus Laboratory (T.D.L.), Imperial Cancer Research Fund, London, and the Department of Pathology (S.M.S.), University of Washington, Seattle.
Correspondence to Dr Martin R. Bennett, Unit of Cardiovascular Medicine, University of Cambridge Clinical School of Medicine, Department of Medicine, Addenbrooke's Hospital, Hills Road, Cambridge, CB2 2QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk © 1997 American Heart Association, Inc.
Abstract The recent demonstration that apoptosis of vascular smooth muscle cells (VSMCs) occurs in human atherosclerotic plaques suggests that VSMC apoptosis may promote plaque rupture and subsequent myocardial infarction. In culture, human plaque VSMCs show higher rates of apoptosis than VSMCs from normal vessels, although the mechanism of this effect is unknown. In earlier studies, we have shown that the tumor suppressor gene p53 regulates apoptosis of rat VSMCs after deregulated cell cycle control. We therefore analyzed p53 function in cultured VSMCs derived from human coronary plaques or the media of normal coronary arteries. VSMCs with reduced or increased p53 activity were created by infecting VSMCs with retroviruses containing a dominant-negative p53 minigene or a chimeric p53 protein (p53TMER), which could be activated pharmacologically. Basal p53 protein expression and transcriptional activity were similar in plaque and normal VSMCs, and suppression of p53 activity blocked growth arrest in response to DNA damage in both VSMC types. In contrast, suppression of p53 activity failed to block apoptosis of plaque or normal VSMCs in low- or high-serum conditions or after DNA damage. Furthermore, in plaque VSMCs, p53 overexpression induced apoptosis in all conditions tested and also induced growth arrest. p53-mediated apoptosis was independent of new gene transcription or protein synthesis but was suppressed by prior growth arrest of cells, indicating that growth status can regulate sensitivity to p53-mediated apoptosis. No effect of increased p53 activity was seen in normal VSMCs. We conclude that VSMCs from human plaques have an increased sensitivity to p53-mediated apoptosis compared with normal VSMCs. Our data also suggest that the mechanism of p53-mediated apoptosis of plaque VSMCs may be distinct from that inducing growth arrest.
Key Words: p53 • apoptosis • atherosclerosis • restenosis • cell cycle
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