Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Research Article
  • Published:

Wild-type p53 gene transfer inhibits neointima formation in human saphenous vein by modulation of smooth muscle cell migration and induction of apoptosis

Gene Therapy volume 8, pages 668–676 (2001)Cite this article

Abstract

Patency of autologous human saphenous vein coronary artery bypass grafts (CABG) is compromised by intimal thickening and superimposed atherosclerosis, caused by migration of vascular smooth muscle cells (SMC) to the intima where they proliferate. Here, using adenoviral transfer, we have targeted SMCs using wild-type p53 (wt p53) overexpression. Initial in vitro analyses demonstrated that wt p53 overexpression had no effect on SMC proliferation but promoted apoptosis, which was inhibited by co-expression of bcl2 or crmA. Wt p53 inhibited SMC invasion through reconstituted matrices, a phenotype not affected by bcl2 or crmA. Overexpression of wt p53 in human saphenous vein before organ culture significantly induced apoptosis (P < 0.01, Student's t test) without affecting proliferation rates either in the media or in the intima. SMC migration was, however, significantly reduced by wt p53 (P < 0.01, Student's t test). Intimal thickening and the number of neointimal cells were reduced by 89% and 73%, respectively, after 14 days (P < 0.01 and P < 0.001, respectively, Student's t test). This study demonstrates that overexpression of wt p53 promotes apoptosis and inhibits migration of SMC leading to reduced intimal thickening. This maybe a useful approach for increasing patency rates in CABG procedures in the clinic.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7

Similar content being viewed by others

References

  1. Izzat M, West R, Bryan A . Coronary artery bypass surgery: current practice in the United Kingdom Br Heart J 1994 71: 382–385

    Article  CAS  Google Scholar 

  2. Marwick C . Coronary bypass grafting: economics, including rehabilitation Curr Opin Cardiol 1994 9: 635–640

    Article  CAS  Google Scholar 

  3. Campeau L et al. Atherosclerosis and late closure of aortocoronary saphenous vein grafts: sequential angiographic studies at 2 weeks, 1 year, 5 to 7 years and 10 to 12 years after surgery Circulation 1983 68: II–1s–II-7s

    Google Scholar 

  4. Bryan A, Angelini G . The biology of saphenous vein graft occlusion: etiology and strategies for prevention Curr Opin Cardiol 1994 9: 641–649

    Article  CAS  Google Scholar 

  5. Davies M, Hagen P-O . Pathobiology of intimal hyperplasia: a review Eur J Vasc Surg 1995 9: 7–18

    Article  Google Scholar 

  6. Baker A, Mehta D, George S, Angelini G . Prevention of vein graft failure: potential applications for gene therapy Cardiovasc Res 1997 35: 442–450

    Article  CAS  Google Scholar 

  7. Cable D et al. The role of gene therapy for intimal hyperplasia of bypass grafts Circulation 1999 100: II–392–II-396

    Google Scholar 

  8. George SJ, Baker AH, Angelini GD, Newby AC . Gene transfer of tissue inhibitor of metalloproteinase-2 inhibits metalloproteinase activity and neointima formation in human saphenous veins Gene Therapy 1998 5: 1552–1560

    Article  CAS  Google Scholar 

  9. George SJ et al. Adenovirus-mediated gene transfer of the human TIMP-1 gene inhibits SMC migration and neointima formation in human saphenous vein Hum Gene Ther 1998 9: 867–877

    Article  CAS  Google Scholar 

  10. Mann MJ et al. Genetic engineering of vein grafts resistant to atherosclerosis Proc Nat Acad Sci USA 1995 92: 4502–4506

    Article  CAS  Google Scholar 

  11. Mann MJ et al. Cell cycle inhibition preserves endothelial function in genetically engineered rabbit vein grafts J Clin Invest 1997 99: 1295–1301

    Article  CAS  Google Scholar 

  12. Bai H et al. Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene Gene Therapy 1998 5: 761–769

    Article  CAS  Google Scholar 

  13. George SJ et al. Inhibition of late vein graft neointima formation in human and porcine models by adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-3 Circulation 2000 101: 296–304

    Article  CAS  Google Scholar 

  14. Mann M et al. Ex vivo gene therapy of human vascular bypass grafts with E2F decoy: the PREVENT single-centre, randomised, controlled trial Lancet 1999 354: 1493–1498

    Article  CAS  Google Scholar 

  15. George SJ, Zaltsman AB, Newby AC . Surgical preparative injury and neointima formation increase MMP-9 expression and MMP-2 activation in human saphenous vein Cardiovasc Res 1997 33: 447–459

    Article  CAS  Google Scholar 

  16. Steg P et al. Reduction of restenosis after angioplasty in an atheromatous rabbit model by suicide gene therapy Circulation 1997 96: 408–411

    Article  CAS  Google Scholar 

  17. Guzman R et al. In vivo suppression of injury-induced vascular smooth muscle cell accumulation using adenovirus-mediated transfer of the herpes simplex virus thymidine kinase Proc Natl Acad Sci USA 1994 91: 10732–10736

    Article  CAS  Google Scholar 

  18. Ohno T et al. Gene therapy for vascular smooth muscle cell proliferation after arterial injury Science 1994 265: 781–784

    Article  CAS  Google Scholar 

  19. Katayose D, Wersto R, Cowan K, Seth P . Consequences of p53 gene expression by adenovirus vector on cell cycle arrest and apoptosis in human aortic vascular smooth muscle cells Biochem Biophys Res Commun 1995 215: 446–451

    Article  CAS  Google Scholar 

  20. Yonemitsu Y et al. Transfer of wild-type p53 gene effectively inhibits vascular smooth muscle cell proliferation in vitro and in vivo Circ Res 1998 82: 147–156

    Article  CAS  Google Scholar 

  21. Aoki M et al. Inhibition of the p53 tumour 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

    Article  CAS  Google Scholar 

  22. Bennett MR, Littlewood TD, Schwartz SM, Weissberg PL . Increased sensitivity of human vascular smooth muscle cells from atherosclerotic plaques to p53-mediated apoptosis Circ Res 1997 81: 591–599

    Article  CAS  Google Scholar 

  23. Toschi E et al. Wild-type p53 gene transfer inhibits invasion and reduces matrix metalloproteinase-2 levels on p53-mutated human melanoma cells J Invest Dermatol 2000 114: 1–7

    Article  Google Scholar 

  24. Soyombo AA et al. Intimal proliferation in an organ culture of human saphenous vien Am J Pathol 1990 137: 1401–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Ricconi T et al. Adenovirus-mediated wild-type p53 overexpression inhibits endothelial cell differentiation in vitro and angiogenesis in vivo Gene Therapy 1998 5: 747–754

    Article  Google Scholar 

  26. Pierzchalski P et al. p53 induces myocyte apoptosis via activation of the renin-angiotensin system Exp Cell Res 1997 234: 57–65

    Article  CAS  Google Scholar 

  27. Wilkinson GWG, Akrigg A . Constitutive and enhanced expression from the CMV major IE promoter in a defective adenovirus vector Nucleic Acids Res 1992 20: 2233–2239

    Article  CAS  Google Scholar 

  28. Baker AH et al. Development of recombinant adenoviruses that drive high level expression of the human metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 and -2 genes: characterization of their infection into rabbit smooth muscle cells and human MCF-7 adenocarcinoma cells Matrix Biol 1996 15: 383–395

    Article  CAS  Google Scholar 

  29. Southgate K, Newby AC . Serum-induced proliferation of rabbit aortic smooth muscle cells from the contractile state is inhibited by 8-Br-cAMP but not 8-Br-cGMP Atherosclerosis 1990 82: 113–123

    Article  CAS  Google Scholar 

  30. George S, Fabunmi R, Williams A, Newby A . An essential role for platelet derived growth factor in neointima formation in human saphenous vein in vitro Atherosclerosis 1996 120: 227–240

    Article  Google Scholar 

  31. Pederson DC, Bowyer DE . Endothelial injury and healing in vitro Am J Pathol 1985 119: 264–272

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We wish to thank Mr Jason Johnson and Miss Melanie Smith for technical assistance, Gary Nabel (University of Michigan) for RAdcrmA and Dr James Uney (University of Bristol) for RAdbcl2. The European Biomed2 initiative, the Garfield Weston Foundation, the British Heart Foundation and the Medical Research Council for Great Britain funded this work.

Author information

Author notes

  1. A H Baker

    Present address: Department of Medicine and Therapeutics, University of Glasgow, Western Infirmary, Glasgow, G11 6NT, UK

Authors and Affiliations

  1. Bristol Heart Institute, University of Bristol, Bristol Royal Infirmary, Bristol, BS2 8HW, UK

    S J George, G D Angelini & A H Baker

  2. Laboratorio di Patologia Vascolare, Istituto Dermopatico dell' Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy

    M C Capogrossi

Authors
  1. S J George
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G D Angelini
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M C Capogrossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A H Baker
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

George, S., Angelini, G., Capogrossi, M. 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 8, 668–676 (2001). https://doi.org/10.1038/sj.gt.3301431

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gt.3301431

Keywords

This article is cited by

Search

Advanced search

Quick links