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

Author:
  • W Dichtl
  • J Dulak
  • M Frick
  • HF Alber
  • SP Schwarzacher
  • Mikko Ares
  • Jan Nilsson
  • O Pachinger
  • F Weidinger
Publishing year: 2003
Language: English
Pages: 58-63
Publication/Series: Arteriosclerosis, Thrombosis and Vascular Biology
Volume: 23
Issue: 1
Document type: Journal article
Publisher: Lippincott Williams Wilkins Hagerstown, MD

Abstract english

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.

Keywords

  • Cardiac and Cardiovascular Systems
  • activator protein-1
  • hypoxia-inducible
  • vascular endothelial growth factor
  • factor-1 alpha
  • statins
  • nuclear factor-kappa B

Other

Published
  • Cardiovascular Research - Immunity and Atherosclerosis
  • ISSN: 1524-4636
E-mail: jan [dot] nilsson [at] med [dot] lu [dot] se

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