Skip to main content
NCBI home page
Clinical Cardiology logoLink to Clinical Cardiology
. 2009 Dec 21;32(12):705–710. doi: 10.1002/clc.20639

p53 Levels Positively Correlate with Carotid Intima‐media Thickness in Patients with Subclinical Atherosclerosis

Wenqiang Chen 1,✉, Fen Wang 2, Zongxin Li 1, Xiaobo Huang 1, Ningqun Wang 1, Zhizhi Dong 1, Ping Sun 1
PMCID: PMC6652994  PMID: 20027663

Abstract

Background

The level of circulating p53 is related to inflammation in asymptomatic subjects with cardiovascular risk factors. Whether p53 is associated with the severity of atherosclerosis remains to be determined.

Hypothesis

This study examines the relationship of systemic p53 levels with atherosclerotic risk factors and subclinical atherosclerosis.

Methods

Circulating levels of p53 and markers of inflammation were measured in 356 subjects with cardiovascular risk factors but who were free from clinical cardiovascular disease. Subclinical atherosclerosis was evaluated by both the mean carotid intima‐media thickness (IMT) and the presence of atherosclerotic plaques with the use of B‐mode ultrasound in all subjects.

Results

p53 levels were positively correlated with age (r = 0.382, P < 0.001), intercellular adhesion molecular‐1 (ICAM‐1; r = 0.510, P < 0.01), vascular cell adhesion molecular‐1 (VCAM‐1; r = 0.497, P < 0.01), E‐selectin (r = 0.337, P < 0.01), and carotid IMT (r = 0.594, P < 0.01). The association between p53 and IMT remained significant in multiple regression analysis (P < 0.01) when controlling for traditional atherosclerotic risk factors and inflammatory markers.

Conclusion

Higher plasma p53 levels were associated with an increase in inflammatory markers, as well as increased carotid IMT. Circulating p53 may be useful in identifying subclinical atherosclerosis in subjects symptomatically free from cardiovascular disease. Copyright © 2009 Wiley Periodicals, Inc.

Full Text

The Full Text of this article is available as a PDF (125.5 KB).

References

  • 1. O'Leary DH, Polak JF, Kronmal RA, et al. Carotid‐artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999; 340: 14–22. [DOI] [PubMed] [Google Scholar]
  • 2. Minamino T, Miyauchi H, Yoshida T, et al. Endothelial cell senescence in human atherosclerosis role of telomere in endothelial dysfunction. Circulation 2002; 105: 1541–1544. [DOI] [PubMed] [Google Scholar]
  • 3. Brandes RP, Fleming I, Busse R. Endothelial aging. Cardiovasc Res 2005; 66: 286–294. [DOI] [PubMed] [Google Scholar]
  • 4. Fenton M, Barker S, Kurz DJ, et al. Cellular senescence after single and repeated balloon catheter denudations of rabbit carotid arteries. Arterioscler Thromb Vasc Biol 2001; 21: 220–226. [DOI] [PubMed] [Google Scholar]
  • 5. Liao S, Curci JA, Kelley BJ, et al. Accelerated replicative senescence of medial smooth muscle cells derived from abdominal aortic aneurysms compared to the adjacent inferior mesenteric artery. J Surg Res 2000; 92: 85–95. [DOI] [PubMed] [Google Scholar]
  • 6. Sherr CJ, DePinho RA. Cellular senescence: mitotic clock or culture shock? Cell 2000; 102: 407–410. [DOI] [PubMed] [Google Scholar]
  • 7. Satyanarayana A, Wiemann SU, Buer J, et al. Telomere shortening impairs organ regeneration by inhibiting cell cycle re‐entry of a subpopulation of cells. EMBO J 2003; 22: 4003–4013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8. Donehower LA. Does p53 affect organismal aging? J Cell Physiol 2002; 192: 23–33. [DOI] [PubMed] [Google Scholar]
  • 9. Lavezzi AM, Milei J, Grana DR, et al. Expression of c‐fos, p53 and PCNA in the unstable atherosclerotic carotid plaque. Int J Cardiol 2003; 92: 59–63. [DOI] [PubMed] [Google Scholar]
  • 10. Aoki M, Morishita R, Matsushita H, et al. Inhibition of the p53 tumor suppressor gene results in growth of human aortic vascular smooth muscle cells. Potential role of p53 in regulation of vascular smooth muscle cell growth. Hypertension 1999; 34: 192–200. [DOI] [PubMed] [Google Scholar]
  • 11. Mancini GB, Dahlöf B, Díez J. Surrogate markers for cardiovascular disease: structural markers. Circulation 2004; 109: IV22–30. [DOI] [PubMed] [Google Scholar]
  • 12. Martinet W, Knaapen MW, De Meyer GR, et al. Elevated levels of oxidative DNA damage and DNA repair enzymes in human atherosclerotic plaques. Circulation 2002; 106: 927–932. [DOI] [PubMed] [Google Scholar]
  • 13. Ihling C, Haendeler J, Menzel G, et al. Co‐expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. J Pathol 1998; 185: 303–312. [DOI] [PubMed] [Google Scholar]
  • 14. Saito H, Papaconstantinou J. Age‐associated differences in cardiovascular inflammatory gene induction during endotoxic stress. J Biol Chem 2001; 276: 29307–29312. [DOI] [PubMed] [Google Scholar]
  • 15.European Society of Hypertension‐European Society of Cardiology Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology Guidelines for the Management of Arterial Hypertension. J Hypertens 2003; 21: 1011–1053. [DOI] [PubMed] [Google Scholar]
  • 16. Stenger JE, Mayr GA, Mann K, et al. Formation of stable p53 homotetramers and multiples of tetramers. Mol Carcinog 1992; 52: 102–106. [DOI] [PubMed] [Google Scholar]
  • 17. Geng YJ. Biologic effect and molecular regulation of vascular apoptosis in atherosclerosis. Curr Atheroscler Rep 2001; 3: 234–242. [DOI] [PubMed] [Google Scholar]
  • 18. Saam T, Yuan C, Chu B, et al. Predictors of carotid atherosclerotic plaque progression as measured by noninvasive magnetic resonance imaging. Atherosclerosis 2007; 194: e34–42. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19. Lutgens E, de Muinck ED, Kitslaar PJ, et al. Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques. Cardiovasc Res 1999; 41: 473–479. [DOI] [PubMed] [Google Scholar]
  • 20. van Vlijmen BJ, Gerritsen G, Franken AL, et al. Macrophage p53 deficiency leads to enhanced atherosclerosis in APOE* 3‐Leiden transgenic mice. Circ Res 2001; 88: 780–786. [DOI] [PubMed] [Google Scholar]
  • 21. Mercer J, Mahmoudi M, Bennett M. DNA damage, p53, apoptosis and vascular disease. Mutat Res 2007; 621: 75–86. [DOI] [PubMed] [Google Scholar]
  • 22. Tabas I. p53 and atherosclerosis. Circ Res 2001; 88: 747–749. [DOI] [PubMed] [Google Scholar]
  • 23. Sanz‐González SM, Barquín L, García‐Cao I, et al. Increased p53 gene dosage reduces neointimal thickening induced by mechanical injury but has no effect on native atherosclerosis. Cardiovasc Res 2007; 75: 803–812. [DOI] [PubMed] [Google Scholar]
  • 24. Ihling C, Haendeler J, Menzel G, et al. Co‐expression of p53 and MDM2 in human atherosclerosis: implications for the regulation of cellularity of atherosclerotic lesions. J Pathol 1998; 185: 303–312. [DOI] [PubMed] [Google Scholar]
  • 25. Scheinman M, Ascher E, Levi GS, et al. p53 gene transfer to the injured rat carotid artery decreases neointimal formation. J Vasc Surg 1999; 29: 360–369. [DOI] [PubMed] [Google Scholar]
  • 26. George SJ, Angelini GD, Capogrossi MC, et al. Wild‐type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis. Gene Ther 2001; 8: 668–676. [DOI] [PubMed] [Google Scholar]
  • 27. Matsushita H, Morishita R, Aoki M, et al. Transfection of antisense p53 tumor suppressor gene oligodeoxynucleotides into rat carotid artery results in abnormal growth of vascular smooth muscle cells. Circulation 2000; 101: 1447–1452. [DOI] [PubMed] [Google Scholar]
  • 28. Ihling C, Menzel G, Wellens E, et al. Topographical association between the cyclin‐dependent kinases inhibitor P21, p53 accumulation, and cellular proliferation in human atherosclerotic tissue. Arterioscler Thromb Vasc Biol 1997; 17: 2218–2224. [DOI] [PubMed] [Google Scholar]
  • 29. Kinscherf R, Claus R, Wagner M, et al. Apoptosis caused by oxidized LDL is manganese superoxide dismutase and p53 dependent. FASEB J 1998; 12: 461–467. [DOI] [PubMed] [Google Scholar]
  • 30. Lewis JM, Truong TN, Schwartz MA. Integrins regulate the apoptotic response to DNA damage through modulation of p53. Proc Natl Acad Sci USA 2002; 99: 3627–3632. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Gorgoulis VG, Zacharatos P, Kotsinas A, et al. p53 activates ICAM‐1 (CD54) expression in an NF‐kappaB‐independent manner. EMBO J 2003; 22: 1567–1578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Huo Y, Ley K. Adhesion molecules and atherogenesis. Acta Physiol Scand 2001; 173: 35–43. [DOI] [PubMed] [Google Scholar]
  • 33. Tzoulaki I, Murray GD, Lee AJ, et al. C‐reactive protein, interleukin‐6, and soluble adhesion molecules as predictors of progressive peripheral atherosclerosis in the General Population Edinburgh Artery Study. Circulation 2005; 112: 976–983. [DOI] [PubMed] [Google Scholar]
  • 34. Zhou X, Perez F, Han K, et al. Clonal senescence alters endothelial ICAM‐1 function. Mech Ageing Dev 2006; 127: 779–785. [DOI] [PubMed] [Google Scholar]
  • 35. Mercer J, Mahmoudi M, Bennett M. DNA damage, p53, apoptosis and vascular disease. Mutat Res 2007; 621: 75–86. [DOI] [PubMed] [Google Scholar]
  • 36. Yuan Y, Verna LK, Wang NP, et al. Cholesterol enrichment upregulates intercellular adhesion molecule‐1 in human vascular endothelial cells. Biochim Biophys Acta 2001; 1534: 139–148. [DOI] [PubMed] [Google Scholar]
  • 37. Gorgoulis VG, Pratsinis H, Zacharatos P, et al. p53‐dependent ICAM‐1 overexpression in senescent human cells identified in atherosclerotic lesions. Lab Invest 2005; 85: 502–511. [DOI] [PubMed] [Google Scholar]
  • 38. Tanaka Y, Nomi M, Fujii K, et al. Intercellular adhesion molecule 1 underlies the functional heterogeneity of synovial cells in patients with rheumatoid arthritis: involvement of cell cycle machinery. Arthritis Rheum 2000; 43: 2513–2522. [DOI] [PubMed] [Google Scholar]
  • 39. Aupperle KR, Boyle DL, Hendrix M, et al. Regulation of synoviocyte proliferation, apoptosis, and invasion by the p53 tumor suppressor gene. Am J Pathol 1998; 152: 1091–1098. [PMC free article] [PubMed] [Google Scholar]
  • 40. Vaishnaw AK, McNally JD, Elkon KB. Apoptosis in the rheumatic diseases. Arthritis Rheum 1997; 40: 1917–1927. [DOI] [PubMed] [Google Scholar]

Articles from Clinical Cardiology are provided here courtesy of Wiley

RESOURCES