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

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 292; no. 6; pp. H2935 - H2943
• Main Authors: Torella, Daniele, Curcio, Antonio, Gasparri, Cosimo, Galuppo, Valentina, Serio, Daniela De, Surace, Francesca C, Cavaliere, Anna Lucia, Leone, Angelo, Coppola, Carmela, Ellison, Georgina M, Indolfi, Ciro
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.06.2007
• Subjects: Angioplasty, Balloon - adverse effects; Animals; Aorta - drug effects; Aorta - metabolism; Cardiovascular Agents - administration & dosage; Cardiovascular Agents - pharmacology; Cardiovascular Agents - therapeutic use; Carotid Artery Injuries - etiology; Carotid Artery Injuries - pathology; Carotid Artery Injuries - prevention & control; Carotid Stenosis - etiology; Carotid Stenosis - pathology; Carotid Stenosis - prevention & control; Cell growth; Cell Proliferation - drug effects; Cells, Cultured; Clinical outcomes; Disease Models, Animal; Dose-Response Relationship, Drug; Drug therapy; Feasibility Studies; Hyperplasia; Inhibitor drugs; Janus Kinase 2 - metabolism; Male; Molecules; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - pathology; Muscular system; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Phosphorylation; Prosthesis Design; Rabbits; Rats; Rats, Wistar; RNA, Antisense - genetics; RNA, Antisense - metabolism; Rodents; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - metabolism; Stents; Stents - adverse effects; Time Factors; Transfection; Tunica Intima - drug effects; Tunica Intima - pathology; Vidarabine - administration & dosage; Vidarabine - analogs & derivatives; Vidarabine - pharmacology; Vidarabine - therapeutic use
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00887.2006

1 Laboratory of Molecular and Cellular Cardiology, Magna Graecia University, Catanzaro, Italy; 2 The Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom; and 3 Ospedale Civile Immacolata Concezione, Piove Di Sacco, Padova, Italy Submitted 17 August 2006 ; accepted in final form 2 February 2007 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. signal transduction; drug-eluting stents; smooth muscle cells Address for reprint requests and other correspondence: C. Indolfi, Chief, Division of Cardiology, Laboratory of Molecular and Cellular Cardiology, Dept. of Experimental and Clinical Medicine, Magna Graecia Univ., Campus Germaneto, Catanzaro 88100, Italy (e-mail: indolfi{at}unicz.it )