Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene (original) (raw)

Gene Therapy volume 5, pages 761–769 (1998) Cite this article

Abstract

The senescent cell-derived inhibitor (sdi)-1 (p21) protein has been identified as a downstream mediator of the tumor suppressor p53 in the cell cycle regulation. In this study, we focused on the function of sdi-1 gene in inhibiting vascular smooth muscle cell (VSMC) proliferation after vein grafting in a rabbit model. To test the hypothesis, we transfected human sdi-1 gene by an intra-operative approach. Accompanied by markedly increased sdi-1 protein, the significant increase in PCNA-stained VSMCs in vein grafts was inhibited by transfection of sdi-1 gene. Moreover, at 2 weeks after transfection, transfer of sdi-1 gene resulted in a significant inhibition in neointimal formation, compared with control vector. Of importance, immunohistological studies determining the expression pattern of myosin heavy isoforms, adult type specific SM2 and embryonic specific SMemb/NMHC-B, demonstrated expression of the adult phenotype of VSMCs in the neointima of sdi-1 gene-transfected vein grafts at 2 weeks after the operation, while the neointima was predominantly composed of embryonic phenotype of VSMCs in the control grafts. Overall, these results demonstrate that a single intraluminal incubation of human sdi-1 gene can result in a significant inhibition of neointimal formation after vein grafting, associated with phenotypic change of VSMCs from neonatal to adult type in a rabbit model. Inhibition of hyperplasia in a graft model by transfection of sdi-1 gene may be due to the change in VSMC phenotype from neonatal to adult, in addition to the inhibition of VSMC growth.

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Authors and Affiliations

  1. First Department of Surgery, Osaka University Medical School, Japan
    H Bai, T Yamakawa, W Zhang, Y Sawa & H Matsuda
  2. Department of Geriatric Medicine, Osaka University Medical School, Japan
    R Morishita, I Kida, M Aoki, H Matsushita, J Higaki & T Ogihara
  3. Department of Radiation Biophysics, Kobe University, Japan
    A Noda
  4. Second Department of Internal Medicine, Gunma University Medical School, Japan
    R Nagai
  5. Institute for Cellular and Molecular Biology, Osaka University Medical School, Japan
    Y Kaneda

Authors

  1. H Bai
  2. R Morishita
  3. I Kida
  4. T Yamakawa
  5. W Zhang
  6. M Aoki
  7. H Matsushita
  8. A Noda
  9. R Nagai
  10. Y Kaneda
  11. J Higaki
  12. T Ogihara
  13. Y Sawa
  14. H Matsuda

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Bai, H., Morishita, R., Kida, I. et al. Inhibition of intimal hyperplasia after vein grafting by in vivo transfer of human senescent cell-derived inhibitor-1 gene.Gene Ther 5, 761–769 (1998). https://doi.org/10.1038/sj.gt.3300640

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