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

Forte, Amalia; Grossi, Mario LU ; Turczynska, Karolina LU ; Svedberg, Kaj LU ; Rinaldi, Barbara; Donniacuo, Maria; Holm, Anders LU ; Baldetorp, Bo LU ; Vicchio, Mariano and De Feo, Marisa, et al. (2013) In International Journal of Cardiology 168(4). p.3370-3380
Abstract
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... (More)
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. (Less)
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keywords
Restenosis, Negative remodeling, Ornithine decarboxylase, alpha-Difluoromethylornithine, Endothelial cells, Smooth muscle cells
in
International Journal of Cardiology
volume
168
issue
4
pages
3370 - 3380
publisher
Elsevier
external identifiers
  • wos:000326219600044
  • scopus:84886292095
ISSN
0167-5273
DOI
10.1016/j.ijcard.2013.04.153
language
English
LU publication?
yes
id
300a38d8-2aed-43c0-a690-17875348715e (old id 4204000)
date added to LUP
2014-01-03 10:40:43
date last changed
2019-02-20 01:50:58
@article{300a38d8-2aed-43c0-a690-17875348715e,
  abstract     = {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.},
  author       = {Forte, Amalia and Grossi, Mario and Turczynska, Karolina and Svedberg, Kaj and Rinaldi, Barbara and Donniacuo, Maria and Holm, Anders and Baldetorp, Bo and Vicchio, Mariano and De Feo, Marisa and Sante, Pasquale and Galderisi, Umberto and Berrino, Liberato and Rossi, Francesco and Hellstrand, Per and Nilsson, Bengt-Olof and Cipollaro, Marilena},
  issn         = {0167-5273},
  keyword      = {Restenosis,Negative remodeling,Ornithine decarboxylase,alpha-Difluoromethylornithine,Endothelial cells,Smooth muscle cells},
  language     = {eng},
  number       = {4},
  pages        = {3370--3380},
  publisher    = {Elsevier},
  series       = {International Journal of Cardiology},
  title        = {Local inhibition of ornithine decarboxylase reduces vascular stenosis in a murine model of carotid injury},
  url          = {http://dx.doi.org/10.1016/j.ijcard.2013.04.153},
  volume       = {168},
  year         = {2013},
}