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1 Cardiology, Magna Graecia University, Catanzaro, Italy; The Research Institute for Sport & Exercise Sciences, Liverpool John Moores University , Liverpool, United Kingdom
2 Cardiology, Magna Graecia University, Catanzaro, Italy
3 Cardiology, Ospedale Civile, Padova, Italy
4 The Research Institute for Sport & Exercise Sciences, Liverpool John Moores University , Liverpool, United Kingdom
* To whom correspondence should be addressed. E-mail: indolfi{at}unicz.it.
Background: Drug eluting stents (DES) are increasingly used to reduce in-stent restenosis and adverse cardiac events after percutaneous coronary interventions. However, the race for the ideal DES 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 anti-proliferative cellular effects. The aim of the present study was to assess the cellular and molecular effects of Fludarabine on VSMC growth in vitro and in vivo and the feasibility and efficacy of a Fludarabine eluting stent. Methods: 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. In order 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 lab manufactured and tested in a rabbit model of in-stent restenosis. Results: 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 STAT1 activation without affecting other STAT proteins. Conclusions: Fludarabine abolishes VSMC proliferation in vitro and reduces neointimal formation after balloon injury in vivo through specific inhibition of STAT1 activation. Fludarabine-eluting-stents are feasible and effective in reducing in-stent restenosis in rabbits.
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