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HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells

Dichtl, W; Dulak, J; Frick, M; Alber, HF; Schwarzacher, SP; Ares, Mikko LU ; Nilsson, Jan LU ; Pachinger, O and Weidinger, F (2003) In Arteriosclerosis, Thrombosis and Vascular Biology 23(1). p.58-63
Abstract
Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mumol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional... (More)
Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mumol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IkappaB-alpha protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1alpha. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. Conclusions-HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-kappaB, AP-1, and hypoxia-inducible factor-1alpha. These, findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
activator protein-1, hypoxia-inducible, vascular endothelial growth factor, factor-1 alpha, statins, nuclear factor-kappa B
in
Arteriosclerosis, Thrombosis and Vascular Biology
volume
23
issue
1
pages
58 - 63
publisher
American Heart Association
external identifiers
  • pmid:12524225
  • wos:000180366800013
  • scopus:0037233913
ISSN
1524-4636
DOI
10.1161/01.ATV.0000043456.48735.20
language
English
LU publication?
yes
id
da690ce4-4aa7-47c5-b991-ef45fc07c350 (old id 319425)
date added to LUP
2007-08-29 11:59:04
date last changed
2018-05-29 10:32:27
@article{da690ce4-4aa7-47c5-b991-ef45fc07c350,
  abstract     = {Objective-Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results-Simvastatin, atorvastatin, and lovastatin (0.1 to 10 mumol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-kappaB) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-kappaB or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IkappaB-alpha protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1alpha. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. Conclusions-HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-kappaB, AP-1, and hypoxia-inducible factor-1alpha. These, findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.},
  author       = {Dichtl, W and Dulak, J and Frick, M and Alber, HF and Schwarzacher, SP and Ares, Mikko and Nilsson, Jan and Pachinger, O and Weidinger, F},
  issn         = {1524-4636},
  keyword      = {activator protein-1,hypoxia-inducible,vascular endothelial growth factor,factor-1 alpha,statins,nuclear factor-kappa B},
  language     = {eng},
  number       = {1},
  pages        = {58--63},
  publisher    = {American Heart Association},
  series       = {Arteriosclerosis, Thrombosis and Vascular Biology},
  title        = {HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells},
  url          = {http://dx.doi.org/10.1161/01.ATV.0000043456.48735.20},
  volume       = {23},
  year         = {2003},
}