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The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo

Nature Medicine volume 5, pages 335–339 (1999)Cite this article

Abstract

The tumor suppressor protein p53 is an essential molecule in cell proliferation and programmed cell death (apoptosis), and has been postulated to play a principal part in the development of atherosclerosis. We have examined the effect of p53 inactivation on atherogenesis in apoE-knockout mice, an animal model for atherosclerosis1,2. We found that, compared with p53+/+/apoE–/– mice, p53–/–/apoE–/– mice developed considerably accelerated aortic atherosclerosis in the presence of a similar serum cholesterol in response to a high-fat diet. Furthermore, the atherosclerotic lesions in p53–/–/apoE–/– mice had a significant (~280%) increase in cell proliferation rate and an insignificant (~180%) increase in apoptosis compared with those in p53+/+/apoE–/– mice. Our observations indicate that the role of p53 in atherosclerotic lesion development might be associated with its function in cell replication control, and that p53-independent mechanisms can mediate the apoptotic response in atherosclerosis.

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Figure 1: Atherosclerosis in p53+/+/apoE–/– and p53–/–/apoE–/– mice fed a Western-type diet for 10 weeks.
Figure 2: Apoptotic (a and c) and proliferating (b and d) cells in atherosclerotic plaques of apoE-deficient mice fed a Western-type diet for 10 weeks.

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References

  1. Nakashima, Y. et al. ApoE-deficient mice develop lesions of all phases of atherosclerosis throughout the arterial tree. Arterioscler. Thromb. 14, 133–140 (1994).

    Article  CAS  PubMed  Google Scholar 

  2. Reddick, R.L., Zhang, S.H. & Maeda, N. Atherosclerosis in mice lacking Apo E. Evaluation of lesional development and progression. Arterioscler. Thromb. 14, 141–147 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Virchow, R. Cellular Pathology as Based Upon Physiological and Pathological Histology (transl. Frank Chance, 1971) 1–554 (Dover, New York, 1863).

    Google Scholar 

  4. Ross, R. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801–809 (1993).

    Article  CAS  PubMed  Google Scholar 

  5. Geng, Y.-J. & Libby, P. Evidence for apoptosis in advanced human atheroma. Colocalization with interleukin-1β-converting enzyme. Am. J. Pathol. 147, 251–266 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Isner, J.M., Kearney, M., Bortman, S. & Passeri, J. Apoptosis in human atherosclerosis and restenosis. Circulation 91, 2703–2711 (1995).

    Article  CAS  PubMed  Google Scholar 

  7. Han, D.K.M. et al. Evidence for apoptosis in human atherogenesis and in a rat vascular injury model. Am. J. Pathol. 147, 267–277 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Bjàrkerud, S. & Bjàrkerud, B. Apoptosis is abundant in human atherosclerotic lesions, especially in inflammatory cells (macrophages and T cells), and may contribute to the accumulation of gruel and plaque instability. Am. J. Pathol. 149, 367–380 (1996).

    Google Scholar 

  9. Kockx, M.M. Apoptosis in the atherosclerotic plaque. Arterioscler. Thromb. Vascular Biol. 18, 1519–1522 (1998).

    Article  CAS  Google Scholar 

  10. Speir, E. et al. Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265, 391–394 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Zhou, Y.F. et al. Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherecomy. N. Engl. J. Med. 335, 624–630 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Donehower, L.A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992).

    Article  CAS  PubMed  Google Scholar 

  13. Plump, A.S. et al. Severe hypercholesterolemia and atherosclerosis in apolipoprotein E-deficient mice created by homologous recombination in ES cells. Cell 71, 343–353 (1992).

    Article  CAS  PubMed  Google Scholar 

  14. Donehower, L.A. Effects of p53 mutation on tumor progression: recent insights from mouse tumor models. Biochim. Biophys. Acta 1242, 171–176 (1996).

    PubMed  Google Scholar 

  15. Levine, A.J. p53, the cellular gatekeeper for growth and division. Cell 88, 323–331 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Rembold, C. Could atherosclerosis originate from defective smooth muscle cell death (apoptosis)? Persp. Biol. Med. 39, 405–408 (1996).

    Article  CAS  Google Scholar 

  17. Bennett, M.R., Evan, G.I. & Schwartz, S.M. Apoptosis of rat vascular smooth muscle cells is regulated by p53-dependent and -independent pathways. Circ. Res. 77, 266–273 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Ko, L.J. & Prives, C. p53: puzzle and paradigm. Genes Dev. 10, 1054–1072 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Hundley, J.E. et al. Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol. Cell. Biol. 17, 723–731 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Jones, J.M. et al. Absence of p53 in a mouse mammary tumor model promotes tumor cell proliferation without affecting apoptosis. Cell Growth Differ. 8, 829–838 (1997).

    CAS  PubMed  Google Scholar 

  21. Harvey, M. et al. In vitro growth characteristics of embryo fibroblasts isolated from p53-deficient mice. Oncogene 8, 2457–2467 (1993).

    CAS  PubMed  Google Scholar 

  22. Palinski, W. et al. ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Arterioscler. Thromb. 14, 605–616 (1994).

    Article  CAS  PubMed  Google Scholar 

  23. Conover, W.J. Practical Nonparametric Statistics 2nd ed. 213–343 (John Wiley & Sons, New York, 1980).

    Google Scholar 

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Acknowledgements

We thank M.E. DeBakey for his interest and support, L. Donehower for his advice, C. Langston for allowing us to use the video imaging system for these studies, E. Zsigmond for assistance with FPLC, M. Majesky for a critical reading of the paper and E. Boerwinkle of The Human Genetics Center of The University of Texas Health Science Center for assistance with the statistical analysis. This work was supported by an NIH grant (HL-51586).

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  1. Natalia V. Guevara

    Present address: Physical Sciences Department, The University of Texas at Brownsville and Texas Southmost College, 80 Fort Brown, Brownsville, Texas, 78520, USA

Authors and Affiliations

  1. Department of Cell Biology and Medicine, Baylor College of Medicine, Houston, 77030, Texas, USA

    Natalia V. Guevara, Ekaterina I. Antonova & Lawrence Chan

  2. Department of Pathology, Baylor College of Medicine, Houston, 77030, Texas, USA

    Han-Seob Kim

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Guevara, N., Kim, HS., Antonova, E. et al. The absence of p53 accelerates atherosclerosis by increasing cell proliferation in vivo. Nat Med 5, 335–339 (1999). https://doi.org/10.1038/6585

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