This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 96/6/667    most recent 01.RES.0000161069.15577.cav1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mercer, J. Articles by Bennett, M. R. Search for Related Content PubMed PubMed Citation Articles by Mercer, J. Articles by Bennett, M. R. Related Collections Apoptosis Cell biology/structural biology Smooth muscle proliferation and differentiation Mechanism of atherosclerosis/growth factors

(Circulation Research. 2005;96:667.)
© 2005 American Heart Association, Inc.

Integrative Physiology

Endogenous p53 Protects Vascular Smooth Muscle Cells From Apoptosis and Reduces Atherosclerosis in ApoE Knockout Mice

John Mercer, Nichola Figg, Victoria Stoneman, Denise Braganza, Martin R. Bennett

From the Division of Cardiovascular Medicine, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK.

Correspondence to Martin Bennett, Division of Cardiovascular Medicine, University of Cambridge, PO Box 110, Addenbrooke’s Hospital, Cambridge, CB2 2QQ, UK. E-mail mrb{at}mole.bio.cam.ac.uk

Recent studies have indicated that the tumor suppressor gene p53 limits atherosclerosis in animal models; p53 expression is also increased in advanced human plaques compared with normal vessels, where it may induce growth arrest and apoptosis. However, controversy exists as to the role of endogenous levels of p53 in different cell types that comprise plaques. We examined atherosclerotic plaque development and composition in brachiocephalic arteries and aortas of p53^–/–/ApoE^–/– mice versus wild type p53 controls. p53^–/– mice demonstrated increased aortic plaque formation, with increased rates of cell proliferation and reduced rates of apoptosis in brachiocephalic arteries. Although most proliferating cells were monocyte/macrophages, apoptotic cells were both vascular smooth muscle cells (VSMCs) and macrophages. Transplant of p53 bone marrow to p53^–/–/ApoE^–/– mice reduced aortic plaque formation and cell proliferation in brachiocephalic plaques, but also markedly reduced apoptosis. To examine p53 regulation of these processes, we studied proliferation and apoptosis in macrophages, bone marrow stromal cells and VSMCs cultured from these mice. Although endogenous p53 promoted apoptosis in macrophages, it protected VSMCs and stromal cells from death, a hitherto unknown function in these cells, in part by inhibiting DNA damage response enzymes. p53 also inhibited stromal cell expression of VSMC markers. We conclude that endogenous levels of p53 protect VSMCs and stromal cells against apoptosis, while promoting apoptosis in macrophages, and protect against atherosclerosis development.

Key Words: atherosclerosis • apoptosis • cell proliferation

This article has been cited by other articles:

				C.-S. Kim, S.-B. Jung, A. Naqvi, T. A. Hoffman, J. DeRicco, T. Yamamori, M. P. Cole, B.-H. Jeon, and K. Irani P53 Impairs Endothelium-Dependent Vasomotor Function Through Transcriptional Upregulation of P66shc Circ. Res., December 5, 2008; 103(12): 1441 - 1450. [Abstract] [Full Text] [PDF]

				A. B. Gerry and D. S. Leake A moderate reduction in extracellular pH protects macrophages against apoptosis induced by oxidized low density lipoprotein J. Lipid Res., April 1, 2008; 49(4): 782 - 789. [Abstract] [Full Text] [PDF]

				A. Zernecke, J. Bernhagen, and C. Weber Macrophage Migration Inhibitory Factor in Cardiovascular Disease Circulation, March 25, 2008; 117(12): 1594 - 1602. [Abstract] [Full Text] [PDF]

				S. M. Sanz-Gonzalez, L. Barquin, I. Garcia-Cao, M. Roque, J. M. Gonzalez, J. J. Fuster, M. T. Castells, J. M. Flores, M. Serrano, and V. Andres Increased p53 gene dosage reduces neointimal thickening induced by mechanical injury but has no effect on native atherosclerosis Cardiovasc Res, September 1, 2007; 75(4): 803 - 812. [Abstract] [Full Text] [PDF]

				J. Dumont, M. Zureik, D. Cottel, M. Montaye, P. Ducimetiere, P. Amouyel, and T. Brousseau Association of arginase 1 gene polymorphisms with the risk of myocardial infarction and common carotid intima media thickness J. Med. Genet., August 1, 2007; 44(8): 526 - 531. [Abstract] [Full Text] [PDF]

				E. Falk, S. M. Schwartz, Z. S. Galis, and M. E. Rosenfeld Putative Murine Models of Plaque Rupture Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 969 - 972. [Full Text] [PDF]

				S. M. Schwartz, Z. S. Galis, M. E. Rosenfeld, and E. Falk Plaque Rupture in Humans and Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 705 - 713. [Abstract] [Full Text] [PDF]

				C. L. Jackson, M. R. Bennett, E. A.L. Biessen, J. L. Johnson, and R. Krams Assessment of Unstable Atherosclerosis in Mice Arterioscler Thromb Vasc Biol, April 1, 2007; 27(4): 714 - 720. [Abstract] [Full Text] [PDF]

				V. Stoneman, D. Braganza, N. Figg, J. Mercer, R. Lang, M. Goddard, and M. Bennett Monocyte/Macrophage Suppression in CD11b Diphtheria Toxin Receptor Transgenic Mice Differentially Affects Atherogenesis and Established Plaques Circ. Res., March 30, 2007; 100(6): 884 - 893. [Abstract] [Full Text] [PDF]