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Inhibition of Polyamine Formation Antagonizes Vascular Smooth Muscle Cell Proliferation and Preserves the Contractile Phenotype.

Grossi, Mario LU ; Persson, Lo LU ; Swärd, Karl LU ; Turczynska, Karolina LU ; Forte, Amalia; Hellstrand, Per LU and Nilsson, Bengt-Olof LU (2014) In Basic & Clinical Pharmacology & Toxicology 115(5). p.379-388
Abstract
The polyamines putrescine, spermidine and spermine play essential roles in cell proliferation and migration, two processes involved in the development of vascular disease. Thus, intervention with polyamine formation may represent a way to inhibit unwanted vascular smooth muscle cell (VSMC) proliferation. The aim of the present study was to assess the importance of polyamines for VSMC proliferation and vascular contractility. The rate-limiting step in polyamine biosynthesis is catalyzed by ornithine decarboxylase. Treatment with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, reduced DNA synthesis in primary rat VSMCs in a concentration-dependent manner with an IC50 value of 100 μM. Moreover, DFMO... (More)
The polyamines putrescine, spermidine and spermine play essential roles in cell proliferation and migration, two processes involved in the development of vascular disease. Thus, intervention with polyamine formation may represent a way to inhibit unwanted vascular smooth muscle cell (VSMC) proliferation. The aim of the present study was to assess the importance of polyamines for VSMC proliferation and vascular contractility. The rate-limiting step in polyamine biosynthesis is catalyzed by ornithine decarboxylase. Treatment with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, reduced DNA synthesis in primary rat VSMCs in a concentration-dependent manner with an IC50 value of 100 μM. Moreover, DFMO reduced VSMC migration assessed in a scratch assay. The DFMO-induced attenuation of VSMC proliferation was associated with lowered cellular amount of polyamines. The anti-proliferative effect of DFMO was specific since supplementation with polyamines reversed the effect of DFMO on proliferation and normalized cellular polyamine levels. Isometric force recordings in cultured rat tail artery rings showed that DFMO counteracts the decrease in contractility caused by culture with foetal bovine serum as growth stimulant. We conclude that inhibition of polyamine synthesis by DFMO may limit the first wave of cell proliferation and migration, which occurs in the acute phase after vascular injury. Besides its anti-proliferative effect, DFMO may prevent loss of the smooth muscle contractile phenotype in vascular injury. This article is protected by copyright. All rights reserved. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Basic & Clinical Pharmacology & Toxicology
volume
115
issue
5
pages
379 - 388
publisher
Wiley-Blackwell
external identifiers
  • pmid:24666424
  • wos:000344015300002
  • scopus:84897358584
ISSN
1742-7843
DOI
10.1111/bcpt.12237
language
English
LU publication?
yes
id
72704456-96f0-43e9-9c32-f8296fab91b8 (old id 4379730)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24666424?dopt=Abstract
date added to LUP
2014-04-03 22:07:50
date last changed
2017-01-01 03:10:31
@article{72704456-96f0-43e9-9c32-f8296fab91b8,
  abstract     = {The polyamines putrescine, spermidine and spermine play essential roles in cell proliferation and migration, two processes involved in the development of vascular disease. Thus, intervention with polyamine formation may represent a way to inhibit unwanted vascular smooth muscle cell (VSMC) proliferation. The aim of the present study was to assess the importance of polyamines for VSMC proliferation and vascular contractility. The rate-limiting step in polyamine biosynthesis is catalyzed by ornithine decarboxylase. Treatment with α-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, reduced DNA synthesis in primary rat VSMCs in a concentration-dependent manner with an IC50 value of 100 μM. Moreover, DFMO reduced VSMC migration assessed in a scratch assay. The DFMO-induced attenuation of VSMC proliferation was associated with lowered cellular amount of polyamines. The anti-proliferative effect of DFMO was specific since supplementation with polyamines reversed the effect of DFMO on proliferation and normalized cellular polyamine levels. Isometric force recordings in cultured rat tail artery rings showed that DFMO counteracts the decrease in contractility caused by culture with foetal bovine serum as growth stimulant. We conclude that inhibition of polyamine synthesis by DFMO may limit the first wave of cell proliferation and migration, which occurs in the acute phase after vascular injury. Besides its anti-proliferative effect, DFMO may prevent loss of the smooth muscle contractile phenotype in vascular injury. This article is protected by copyright. All rights reserved.},
  author       = {Grossi, Mario and Persson, Lo and Swärd, Karl and Turczynska, Karolina and Forte, Amalia and Hellstrand, Per and Nilsson, Bengt-Olof},
  issn         = {1742-7843},
  language     = {eng},
  number       = {5},
  pages        = {379--388},
  publisher    = {Wiley-Blackwell},
  series       = {Basic & Clinical Pharmacology & Toxicology},
  title        = {Inhibition of Polyamine Formation Antagonizes Vascular Smooth Muscle Cell Proliferation and Preserves the Contractile Phenotype.},
  url          = {http://dx.doi.org/10.1111/bcpt.12237},
  volume       = {115},
  year         = {2014},
}