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Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease

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Abstract

We postulated that activation of a genetic program that tonicaiiy inhibits intimal cell death is a necessary condition for the pathogenesis of vascular disease. Studies of vascular lesions in humans and animal models documented increased expression of the anti-apoptotic gene product Bcl-xL within intimal cells. Downregulation of intimal cell bcl-xL expression with the use of antisense oligonucleotides induced apoptosis and acute regression of vascular lesions. These findings indicate that apoptosis regulatory genes such as bcl-xL are critical determinants of intimal lesion formation and that targeted apoptosis may be a novel therapy for intimal vascular disease.

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References

  1. 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 

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

    CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Bochaton-Piallat, M.L., Gabbiani, F., Redard, M., Desmouliere, A. & Cabbiani, G. Apoptosis participates in cellularity regulation during rat aortic intimal thickening. Am. J. Pathol. 146, 1059–1064 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Sedlak, T.W. et al. Multiple Bcl-2 family members demonstrate selective dimeriza-tionswith Bax. Proc. Natl. Acad. Sci. USA 92, 7834–7838 (1995).

    Article  CAS  Google Scholar 

  7. Gajewski, T.F. & Thompson, C.B. Apoptosis meets signal transduction: Elimination of a BAD influence. Cell 87, 589–592 (1996).

    Article  CAS  Google Scholar 

  8. Golstein, P. Controlling cell death. Science 275, 1081 1082 (1997).

    Article  CAS  Google Scholar 

  9. Cheng, E.H., Levine, B., Boise, L.H., Thompson, C.B. & Hardwick, J.M. Bax-inde-pendent inhibition of apoptosis by Bcl-XL. Nature 379, 554–556 (1996).

    Article  CAS  Google Scholar 

  10. Zha, J. et al. BH3 domain of BAD is required for heterodimerization with BCL-XL and pro-apoptotic activity. J. Biol. Chem. 272, 24101–24104 (1997).

    Article  CAS  Google Scholar 

  11. Chinnaiyan, A.M., O'Rourke, K., Lane, B.R. & Dixit, V.M. Interaction of CED-4 with CED-3 and CED-9: A molecular framework for cell death. Science 275, 122–126 (1997).

    Article  Google Scholar 

  12. Motoyama, N. et al. Massive cell death of immature hematopoietic cells and neurons in bcl-x-deficient mice. Science 267, 1506–1510 (1995).

    Article  CAS  Google Scholar 

  13. Schwartz, S.M., deBlois, D. & O'Brien, E.R. The intima: Soil for atherosclerosis and restenosis. Ore Res. 77, 445–465 (1995).

    CAS  Google Scholar 

  14. Morishita, R. et al. Single intraluminal delivery of antisense cdc2 kinase and prolifer-ating-cell nuclear antigen oligonucleotides results in chronic inhibition of neointimal hyperplasia. Proc. Natl. Acad. Sci. USA 90, 8474–8478 (1993).

    Article  CAS  Google Scholar 

  15. Mann, M. et al. Genetic engineering of vein grafts resistant to atherosclerosis. Proc. Natl. Acad. Sci. USA 92, 4502–4506 (1995).

    Article  CAS  Google Scholar 

  16. Wagner, R.W. Gene inhibition using antisense oligonucleotides. Nature 372, 333–335 (1994).

    Article  CAS  Google Scholar 

  17. Burgess, T.L. et al. The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism. Proc. Natl. Acad. Sci. USA 92, 4051–4055 (1995).

    Article  CAS  Google Scholar 

  18. Boise, L.H. et al. Bcl-x, a bcl-2-related gene that functions as a dominant regulator of apoptotic cell death. Cell 74, 597–608 (1993).

    Article  CAS  Google Scholar 

  19. Minn, A.J., Boise, L.H. & Thompson, C.B. Bcl-x(S) antagonizes the protective effects of Bcl-x(L). J. Biol. Chem. 271, 6306–6312 (1996).

    Article  CAS  Google Scholar 

  20. Faxon, D.P. et al. Acute effects of transluminal angioplasty in three experimental models of atherosclerosis. Arteriosclerosis 2, 125–133 (1982).

    Article  CAS  Google Scholar 

  21. Shinomiya, M., Shirai, K., Saito, Y. & Yoshida, S. Inhibition of intimal thickening of the carotid artery of rabbits and of outgrowth of explants of aorta by probucol. Atherosclerosis 97, 143–148 (1992).

    Article  CAS  Google Scholar 

  22. Morishita, R, et al. Intimal hyperplasia after vascular injury is inhibited by antisense cdk 2 kinase oligonucleotides. J. Clin. Invest. 93, 1458–1464 (1994).

    Article  CAS  Google Scholar 

  23. Pollman, M.J., Yamada, T., Horiuchi, M. & Gibbons, G.H. Vasoactive substances regulate vascular smooth muscle cell apoptosis: Countervailing influences of nitric oxide and angiotensin II. Circ. Res. 79, 748–756 (1996).

    Article  CAS  Google Scholar 

  24. Gavrieli, Y., Sherman, Y. & Ben-Sasson, S.A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J. Cell Biol. 119, 493–501 (1992).

    Article  CAS  Google Scholar 

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Correspondence to Gary H. Gibbons.

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Pollman, M., Hall, J., Mann, M. et al. Inhibition of neointimal cell bcl-x expression induces apoptosis and regression of vascular disease. Nat Med 4, 222–227 (1998). https://doi.org/10.1038/nm0298-222

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  • DOI: https://doi.org/10.1038/nm0298-222

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