Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat

Steven J. Sollott, Linda Cheng, Rebecca R. Pauly, G. Mark Jenkins, Robert E. Monticone, Masafumi Kuzuya, Jeffrey P. Froehlich, Michael T. Crow, Edward G. Lakatta, Eric K. Rowinsky, James L. Kinsella

Research output: Contribution to journalArticle

Abstract

Despite significant improvements in the primary success rate of the medical and surgical treatments for atherosclerotic disease, including angioplasty, bypass grafting, and endarterectomy, secondary failure due to late restenosis continues to occur in 30-50% of individuals. Restenosis and the later stages in atherosclerotic lesions are due to a complex series of fibroproliferative responses to vascular injury involving potent growth- regulatory molecules (such as platelet-derived growth factor and basic fibroblast growth factor) and resulting in vascular smooth muscle cell (VSMC) proliferation, migration, and neointimal accumulation. We show here, based on experiments with both taxol and deuterium oxide, that microtubules are necessary for VSMCs to undergo the multiple transformations contributing to the development of the neointimal fibroproliferative lesion. Taxol was found to interfere both with platelet-derived growth factor-stimulated VSMC migration and with VSMC migration and with VSMC proliferation, at nanomolar levels in vitro. In vivo, taxol prevented medial VSMC proliferation and the neointimal VSMC accumulation in the rat carotid artery after balloon dilatation and endothelial denudation injury. This effect occurred at plasma levels approximately two orders of magnitude lower than that used clinically to treat human malignancy (peak levels achieved in this model were ~ 50-60 nM). Taxol may therefore be of therapeutic value in preventing human restenosis with minimal toxicity.

Original languageEnglish (US)
Pages (from-to)1869-1876
Number of pages8
JournalJournal of Clinical Investigation
Volume95
Issue number4
DOIs
StatePublished - Apr 1995

Keywords

  • atherosclerosis
  • deuterium oxide
  • microtubules
  • restenosis
  • tubulin

ASJC Scopus subject areas

  • Medicine(all)

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    Sollott, S. J., Cheng, L., Pauly, R. R., Jenkins, G. M., Monticone, R. E., Kuzuya, M., Froehlich, J. P., Crow, M. T., Lakatta, E. G., Rowinsky, E. K., & Kinsella, J. L. (1995). Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat. Journal of Clinical Investigation, 95(4), 1869-1876. https://doi.org/10.1172/JCI117867