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Inhibitor of apoptosis protein survivin regulates vascular injury

Nature Medicine volume 8, pages 987–994 (2002)Cite this article

Abstract

Survivin (also termed Birc5) belongs to the family of genes known as inhibitors of apoptosis, and it has been implicated in both prevention of cell death and control of mitosis. The survivin pathway is exploited in cancer, but its potential role in vascular injury is unknown. Here, we show that balloon-mediated arterial injury in rabbits resulted in expression of survivin in vascular cells. Serum or PDGF-AB stimulated survivin expression in cultured smooth-muscle cells (SMCs), which suppressed apoptosis and prevented caspase activation. Adenoviral delivery of a phosphorylation-defective survivin mutant reversed the cytoprotective effect of PDGF in SMCs without affecting mitotic progression, suppressed neointimal formation in wire-injured mouse femoral arteries, and induced vascular cell apoptosis in vivo. These data identify survivin as a critical regulator of SMC apoptosis after acute vascular injury. Disrupting the survivin pathway may provide a novel therapy to limit pathological vessel-wall remodeling.

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Figure 1: Induced survivin expression after vascular injury in rabbits and mice.
Figure 2: PDGF regulates survivin expression in SMCs.
Figure 3: SMC cytoprotection by PDGF or survivin.
Figure 4: Survivin targeting induces apoptosis in serum-stimulated SMCs.
Figure 5: Survivin targeting suppresses neointimal formation after acute vascular injury.
Figure 6: Induction of vascular cell apoptosis by survivin targeting with pAd-T34A.

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References

  1. Hengartner, M.O. The biochemistry of apoptosis. Nature 407, 770–776 (2000).

    Article  CAS  Google Scholar 

  2. Reed, J.C. Dysregulation of apoptosis in cancer. J. Clin. Oncol. 17, 2941–2953 (1999).

    Article  CAS  Google Scholar 

  3. Walsh, K., Smith, R.C. & Kim, H.-S. Vascular cell apoptosis in remodeling, restenosis, and plaque rupture. Circ. Res. 87, 184–188 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Choy, J.C., Granville, D.J., Hunt, D.J. & McManus, B.M. Endothelial cell apoptosis: Biochemical characteristics and potential implications for atherosclerosis. J. Mol. Cell Cardiol. 33, 1673–1690 (2001).

    Article  CAS  Google Scholar 

  6. Perlman, H., Maillard, L., Krasinski, K. & Walsh, K. Evidence for the rapid onset of apoptosis in medial smooth muscle cells after balloon injury. Circulation 95, 981–987 (1997).

    Article  CAS  Google Scholar 

  7. Niemann-Jonsson, A. et al. Increased rate of apoptosis in intimal arterial smooth muscle cells through endogenous activation of TNF receptors. Arterioscler. Thromb. Vasc. Biol. 21, 1909–1914 (2001).

    Article  CAS  Google Scholar 

  8. Schaub, F.J. et al. Fas/FADD-mediated activation of a specific program of inflammatory gene expression in vascular smooth muscle cells. Nature Med. 6, 790–796 (2000).

    Article  CAS  Google Scholar 

  9. Okura, Y. et al. Oxidized low-density lipoprotein is associated with apoptosis of vascular smooth muscle cells in human atherosclerotic plaques. Circulation 102, 2680–2686 (2000).

    Article  CAS  Google Scholar 

  10. Bennett, M.R. Apoptosis of vascular smooth muscle cells in vascular remodelling and atherosclerotic plaque rupture. Cardiovasc. Res. 41, 361–368 (1999).

    Article  CAS  Google Scholar 

  11. Miyamoto, T., Leconte, I., Swain, J.L. & Fox, J.C. Autocrine FGF signaling is required for vascular smooth muscle cell survival in vitro. J. Cell Physiol. 177, 58–67 (1998).

    Article  CAS  Google Scholar 

  12. Obata, H. et al. NF-κB is induced in the nuclei of cultured rat aortic smooth muscle cells by stimulation of various growth factors. Biochem. Biophys. Res. Commun. 224, 27–32 (1996).

    Article  CAS  Google Scholar 

  13. Perlman, H. et al. Adenovirus-encoded hammerhead ribozyme to Bcl-2 inhibits neointimal hyperplasia and induces vascular smooth muscle cell apoptosis. Cardiovasc. Res. 45, 570–578 (2000).

    Article  CAS  Google Scholar 

  14. Hayakawa, Y. et al. Apoptosis and overexpression of bax protein and bax mRNA in smooth muscle cells within intimal hyperplasia of human radial arteries: Analysis with arteriovenous fistulas used for hemodialysis. Arterioscler. Thromb. Vasc. Biol. 19, 2066–2077 (1999).

    Article  CAS  Google Scholar 

  15. Pollman, M.J., Hall, J.L., Mann, M.J., Zhang, L. & Gibbons, G.H. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nature Med. 4, 222–227 (1998).

    Article  CAS  Google Scholar 

  16. Ekhterae, D. et al. Bcl-2 decreases voltage-gated K+ channel activity and enhances survival in vascular smooth muscle cells. Am. J. Physiol. Cell Physiol. 281, C157–165 (2001).

    Article  CAS  Google Scholar 

  17. Deveraux, Q.L. & Reed, J.C. IAP family proteins-suppressors of apoptosis. Genes Dev. 13, 239–252 (1999).

    Article  CAS  Google Scholar 

  18. Altieri, D.C. The molecular basis and potential role of survivin in cancer diagnosis and therapy. Trends Mol. Med. 7, 542–547 (2001).

    Article  CAS  Google Scholar 

  19. Hoffman, W.H., Biade, S., Zilfou, J.T., Chen, J. & Murphy, M. Transcriptional repression of the anti-apoptotic survivin gene by wild type p53. J. Biol. Chem. 277, 3247–3257 (2001).

    Article  Google Scholar 

  20. Tran, J. et al. Marked induction of the IAP family antiapoptotic proteins survivin and XIAP by VEGF in vascular endothelial cells. Biochem. Biophys. Res. Commun. 264, 781–788 (1999).

    Article  CAS  Google Scholar 

  21. O'Connor, D.S. et al. Control of apoptosis during angiogenesis by survivin expression in endothelial cells. Am. J. Pathol. 156, 393–398 (2000).

    Article  CAS  Google Scholar 

  22. Papapetropoulos, A. et al. Angiopoietin-1 inhibits endothelial cell apoptosis via the Akt/survivin pathway. J. Biol. Chem. 275, 9102–9105 (2000).

    Article  CAS  Google Scholar 

  23. Mesri, M. et al. Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am. J. Pathol. 158, 1757–1765 (2001).

    Article  CAS  Google Scholar 

  24. Mesri, M., Wall, N.R., Li, J., Kim, R.W. & Altieri, D.C. Cancer gene therapy using a survivin mutant adenovirus. J. Clin. Invest. 108, 981–990 (2001).

    Article  CAS  Google Scholar 

  25. O'Connor, D.S. et al. Regulation of apoptosis at cell division by p34cdc2 phosphorylation of survivin. Proc. Natl. Acad. Sci. USA 97, 13103–13107 (2000).

    Article  CAS  Google Scholar 

  26. Grossman, D., Kim, P.J., Schechner, J.S. & Altieri, D.C. Inhibition of melanoma tumor growth in vivo by survivin targeting. Proc. Natl. Acad. Sci. USA 98, 635–640 (2001).

    Article  CAS  Google Scholar 

  27. Li, F. et al. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396, 580–584 (1998).

    Article  CAS  Google Scholar 

  28. Carter, B.Z., Milella, M., Altieri, D.C. & Andreeff, M. Cytokine-regulated expression of survivin in myeloid leukemia. Blood 97, 2784–2790 (2001).

    Article  CAS  Google Scholar 

  29. Mahboubi, K. et al. Interleukin-11 up-regulates survivin expression in endothelial cells through a signal transducer and activator of transcription-3 pathway. Lab. Invest. 81, 327–334 (2001).

    Article  CAS  Google Scholar 

  30. Grossman, D. et al. Transgenic expression of survivin in keratinocytes counteracts UVB-induced apoptosis and cooperates with loss of p53. J. Clin. Invest. 108, 991–999 (2001).

    Article  CAS  Google Scholar 

  31. Wheatley, S.P., Carvalho, A., Vagnarelli, P. & Earnshaw, W.C. INCENP is required for proper targeting of Survivin to the centromeres and the anaphase spindle during mitosis. Curr. Biol. 11, 886–890 (2001).

    Article  CAS  Google Scholar 

  32. Fortugno, P. et al. Survivin exists in immunochemically distinct subcellular pools and is involved in spindle microtubule function. J. Cell Sci. (in the press).

  33. Hart, C.E. et al. PDGFbeta receptor blockade inhibits intimal hyperplasia in the baboon. Circulation 99, 564–569 (1999).

    Article  CAS  Google Scholar 

  34. Leppanen, O. et al. Intimal hyperplasia recurs after removal of PDGF-AB and -BB inhibition in the rat carotid artery injury model. Arterioscler. Thromb. Vasc. Biol. 20, E89–95 (2000).

    Article  CAS  Google Scholar 

  35. Charles, R. et al. Ceramide-coated balloon catheters limit neointimal hyperplasia after stretch injury in carotid arteries. Circ. Res. 87, 282–288 (2000).

    Article  CAS  Google Scholar 

  36. Olie, R.A. et al. A novel antisense oligonucleotide targeting survivin expression induces apoptosis and sensitizes lung cancer cells to chemotherapy. Cancer Res. 60, 2805–2809 (2000).

    CAS  PubMed  Google Scholar 

  37. Pennati, M. et al. Ribozyme-mediated attenuation of survivin expression sensitizes human melanoma cells to cisplatin-induced apoptosis. J. Clin. Invest. 109, 285–286 (2002).

    Article  CAS  Google Scholar 

  38. Kanwar, J.R., Shen, W.P., Kanwar, R.K., Berg, R.W. & Krissansen, G.W. Effects of survivin antagonists on growth of established tumors and b7-1 immunogene therapy. J. Natl. Cancer Inst. 93, 1541–1552 (2001).

    Article  CAS  Google Scholar 

  39. Signore, P.E. et al. Complete inhibition of intimal hyperplasia by perivascular delivery of paclitaxel in balloon-injured rat carotid arteries. J. Vasc. Interv. Radiol. 12, 79–88 (2001).

    Article  CAS  Google Scholar 

  40. Sollott, S.J. et al. Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. J. Clin. Invest. 95, 1869–1876 (1995).

    Article  CAS  Google Scholar 

  41. Fischman, D.L. et al. A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. Stent Restenosis Study Investigators. N. Engl. J. Med. 331, 496–501 (1994).

    Article  CAS  Google Scholar 

  42. Plescia, J., Conte, M.S., VanMeter, G., Ambrosini, G. & Altieri, D.C. Molecular identification of the cross-reacting epitope on αMβ2 integrin I domain recognized by anti-αIIbβ3 monoclonal antibody and its involvement in leukocyte adherence. J. Biol. Chem. 273, 20372–20377 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by NIH grants HL54131, CA78810, CA90917 (to D.C.A.), and HL57665 and HL64793 (to W.C.S.).

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Authors and Affiliations

  1. Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA

    Olivier P. Blanc-Brude, Jun Yu, William C. Sessa & Dario C. Altieri

  2. Division of Vascular Surgery, Brigham and Women's Hospital, Harvard Institutes of Medicine, Harvard Medical School, Boston, Massachusetts, USA

    Hector Simosa & Michael S. Conte

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  1. Olivier P. Blanc-Brude
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Correspondence to Dario C. Altieri.

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Blanc-Brude, O., Yu, J., Simosa, H. et al. Inhibitor of apoptosis protein survivin regulates vascular injury. Nat Med 8, 987–994 (2002). https://doi.org/10.1038/nm750

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