title: HMG-CoA reductase inhibitors regulate inflammatory transcription factors in human endothelial and vascular smooth muscle cells.
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.
  
  
  RESULTS
  Simvastatin, atorvastatin, and lovastatin (0.1 to 10 micro mol/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.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, Leopold-Franzens-University Innsbruck, Austria. wolfgang.dichtl@uibk.ac.at
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Dichtl
authors.forename: Jozef
authors.initials: J
authors.lastname: Dulak
authors.forename: Matthias
authors.initials: M
authors.lastname: Frick
authors.forename: Hannes F
authors.initials: HF
authors.lastname: Alber
authors.forename: Severin P
authors.initials: SP
authors.lastname: Schwarzacher
authors.forename: Mikko P S
authors.initials: MP
authors.lastname: Ares
authors.forename: Jan
authors.initials: J
authors.lastname: Nilsson
authors.forename: Otmar
authors.initials: O
authors.lastname: Pachinger
authors.forename: Franz
authors.initials: F
authors.lastname: Weidinger
mesh_terms: D000069059:Atorvastatin; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D004730:Endothelium, Vascular / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins / Q000378:metabolism; D007249:Inflammation / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D008148:Lovastatin / Q000378:metabolism / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis; D011485:Protein Binding / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000096:biosynthesis; D011758:Pyrroles / Q000378:metabolism / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D019821:Simvastatin / Q000378:metabolism / Q000494:pharmacology; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D042461:Vascular Endothelial Growth Factor A
chemical_list: D016228:Endothelial Growth Factors; C497442:HIF1A protein, human; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D017395:Plasminogen Activator Inhibitor 1; D016755:Proto-Oncogene Proteins c-jun; D011758:Pyrroles; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; D000072000:NF-KappaB Inhibitor alpha; D008148:Lovastatin; D000069059:Atorvastatin; D019821:Simvastatin