Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation

Daniele Torella, Antonio Curcio, Cosimo Gasparri, Valentina Galuppo, Daniela De Serio, Francesca C. Surace, Anna Lucia Cavaliere, Angelo Leone, Carmela Coppola, Georgina M. Ellison, Ciro Indolfi

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Drug-eluting stents are increasingly used to reduce in-stent restenosis and adverse cardiac events after percutaneous coronary interventions. However, the race for the ideal drug-eluting stent is still on, with special regard to the best stent-coating system and the most effective and less toxic drug. Fludarabine, a nucleoside analog, has both anti-inflammatory and antiproliferative cellular effects. The aim of the present study was to assess the cellular and molecular effects of fludarabine on vascular smooth muscle cell (VSMC) growth in vitro and in vivo and the feasibility and efficacy of a fludarabine-eluting stent. To study the biomolecular effects of fludarabine on VSMC proliferation in vitro, rat VSMCs were grown in the presence of 50 μM fludarabine or in the absence of the same. To evaluate the in vivo effect of this drug, male Wistar rats underwent balloon injury of the carotid artery, and fludarabine was locally delivered at the time of injury. Finally, fludarabine-eluting stents were in-laboratory manufactured and tested in a rabbit model of in-stent restenosis. Fludarabine markedly inhibited VSMC proliferation in cell culture. Furthermore, fludarabine reduced neointimal formation after balloon angioplasty in a dose-dependent manner, and fludarabine-eluting stents reduced neointimal hyperplasia by ∼50%. These in vitro and in vivo cellular effects were specifically associated with the molecular switch-off of signal transducer and activator of transcription (STAT)-1 activation, without affecting other STAT proteins. Fludarabine abolishes VSMC proliferation in vitro and reduces neointimal formation after balloon injury in vivo through specific inhibition of STAT-1 activation. Fludarabine-eluting stents are feasible and effective in reducing in-stent restenosis in rabbits.

Original languageEnglish
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume292
Issue number6
DOIs
Publication statusPublished - Jun 2007

Fingerprint

STAT1 Transcription Factor
Transcriptional Activation
Hyperplasia
Smooth Muscle
Stents
Vascular Smooth Muscle
Smooth Muscle Myocytes
Drug-Eluting Stents
Cell Proliferation
In Vitro Techniques
fludarabine
STAT Transcription Factors
Carotid Artery Injuries
Rabbits
Balloon Angioplasty
Poisons
Wounds and Injuries
Percutaneous Coronary Intervention
Nucleosides
Pharmaceutical Preparations

Keywords

  • Drug-eluting stents
  • Signal transduction
  • Smooth muscle cells

ASJC Scopus subject areas

  • Physiology

Cite this

Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation. / Torella, Daniele; Curcio, Antonio; Gasparri, Cosimo; Galuppo, Valentina; De Serio, Daniela; Surace, Francesca C.; Cavaliere, Anna Lucia; Leone, Angelo; Coppola, Carmela; Ellison, Georgina M.; Indolfi, Ciro.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 292, No. 6, 06.2007.

Research output: Contribution to journalArticle

Torella, Daniele ; Curcio, Antonio ; Gasparri, Cosimo ; Galuppo, Valentina ; De Serio, Daniela ; Surace, Francesca C. ; Cavaliere, Anna Lucia ; Leone, Angelo ; Coppola, Carmela ; Ellison, Georgina M. ; Indolfi, Ciro. / Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation. In: American Journal of Physiology - Heart and Circulatory Physiology. 2007 ; Vol. 292, No. 6.
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abstract = "Drug-eluting stents are increasingly used to reduce in-stent restenosis and adverse cardiac events after percutaneous coronary interventions. However, the race for the ideal drug-eluting stent is still on, with special regard to the best stent-coating system and the most effective and less toxic drug. Fludarabine, a nucleoside analog, has both anti-inflammatory and antiproliferative cellular effects. The aim of the present study was to assess the cellular and molecular effects of fludarabine on vascular smooth muscle cell (VSMC) growth in vitro and in vivo and the feasibility and efficacy of a fludarabine-eluting stent. To study the biomolecular effects of fludarabine on VSMC proliferation in vitro, rat VSMCs were grown in the presence of 50 μM fludarabine or in the absence of the same. To evaluate the in vivo effect of this drug, male Wistar rats underwent balloon injury of the carotid artery, and fludarabine was locally delivered at the time of injury. Finally, fludarabine-eluting stents were in-laboratory manufactured and tested in a rabbit model of in-stent restenosis. Fludarabine markedly inhibited VSMC proliferation in cell culture. Furthermore, fludarabine reduced neointimal formation after balloon angioplasty in a dose-dependent manner, and fludarabine-eluting stents reduced neointimal hyperplasia by ∼50{\%}. These in vitro and in vivo cellular effects were specifically associated with the molecular switch-off of signal transducer and activator of transcription (STAT)-1 activation, without affecting other STAT proteins. Fludarabine abolishes VSMC proliferation in vitro and reduces neointimal formation after balloon injury in vivo through specific inhibition of STAT-1 activation. Fludarabine-eluting stents are feasible and effective in reducing in-stent restenosis in rabbits.",
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AU - De Serio, Daniela

AU - Surace, Francesca C.

AU - Cavaliere, Anna Lucia

AU - Leone, Angelo

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AU - Ellison, Georgina M.

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