Increased Sensitivity of Human Vascular Smooth Muscle Cells From Atherosclerotic Plaques to p53-Mediated Apoptosis

Author:

Bennett Martin R.1,Littlewood Trevor D.1,Schwartz Stephen M.1,Weissberg Peter L.1

Affiliation:

1. 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.

Abstract

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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

Reference53 articles.

Cited by 114 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3