Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury

Summary, in English

Objectives: Polyamines are organic polycations playing an essential role in cell proliferation and differentiation, as well as in cell contractility, migration and apoptosis. These processes are known to contribute to restenosis, a pathophysiological process often occurring in patients submitted to revascularization procedures. We aimed to test the effect of alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, on vascular cell pathophysiology in vitro and in a rat model of carotid arteriotomy-induced (re) stenosis. Methods: The effect of DFMO on primary rat smooth muscle cells (SMCs) and mouse microvascular bEnd. 3 endothelial cells (ECs) was evaluated through the analysis of DNA synthesis, polyamine concentration, cell viability, cell cycle phase distribution and by RT-PCR targeting cyclins and genes belonging to the polyamine pathway. The effect of DFMO was then evaluated in arteriotomy-injured rat carotids through the analysis of cell proliferation and apoptosis, RT-PCR and immunohistochemical analysis of differential gene expression. Results: DFMO showed a differential effect on SMCs and on ECs, with a marked, sustained anti-proliferative effect of DFMO at 3 and 8 days of treatment on SMCs and a less pronounced, late effect on bEnd. 3 ECs at 8 days of DFMO treatment. DFMO applied perivascularly in pluronic gel at arteriotomy site reduced subsequent cell proliferation and preserved smooth muscle differentiation without affecting the endothelial coverage. Lumen area in DFMO-treated carotids was 49% greater than in control arteries 4 weeks after injury. Conclusions: Our data support the key role of polyamines in restenosis and suggest a novel therapeutic approach for this pathophysiological process. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

• Författare: Amalia Forte; Mario Grossi; Karolina Turczynska; Kaj Svedberg; Barbara Rinaldi; Maria Donniacuo; Anders Holm; Bo Baldetorp; Mariano Vicchio; Marisa De Feo; Pasquale Sante; Umberto Galderisi; Liberato Berrino; Francesco Rossi; Per Hellstrand; Bengt-Olof Nilsson; Marilena Cipollaro
• Avdelning/ar: Kärlfysiologi; Bröstcancer-genetik
• Publiceringsår: 2013
• Språk: Engelska
• Sidor: 3370-3380
• Publikation/Tidskrift/Serie: International Journal of Cardiology
• Volym: 168
• Issue: 4
• Fulltext: - 24 MB; Download statistics
• Länkar: http://dx.doi.org/10.1016/j.ijcard.2013.04.153
• Dokumenttyp: Artikel i tidskrift
• Förlag: Elsevier
• Ämne: Cardiac and Cardiovascular Systems
• Nyckelord: Restenosis; Negative remodeling; Ornithine decarboxylase; alpha-Difluoromethylornithine; Endothelial cells; Smooth muscle cells
• Status: Published
• Forskningsgrupp: Vascular Physiology
• ISBN/ISSN/Övrigt: ISSN: 0167-5273