title: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors increase the binding activity and nuclear level of Oct-1 in mononuclear cells.
abstract: 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) are drugs very effective to decrease low-density lipoprotein (LDL) cholesterol. In addition, a number of studies suggest that statins have other beneficial clinical effects beyond cholesterol lowering. We recently reported that statins decrease nuclear factor kappa B (NF-kappaB) binding activity in monocytes and vascular smooth muscle cells. We now explored the effect of two different statins, simvastatin and atorvastatin, in the activation of the octamer transcription factor Oct-1 on the monocytic cell line THP-1. Oct-1 is a nuclear factor that represses the transcription of proinflammatory genes such as interleukin-8, CD11c/CD18, vascular cell adhesion molecule-1 (VCAM-1) and platelet endothelial cell adhesion molecule-1 (PECAM-1). Low concentrations of both statins increased Oct-1 DNA binding activity (electrophoretic mobility shift assay) that was resolved into two specific bands. The upper one was supershifted by preincubation of nuclear extracts with anti-Oct-1 antibody. The lower one was supershifted by preincubation of nuclear extracts with an anti-Oct-2 antibody, also partially competed with 100 mol/l excess of cold activator protein-1 (AP-1) and attenuated by anti-c-Jun antibody. Both statins increased Oct-1 and Oct-2 nuclear protein levels (Western blot). In contrast, neither had any effect on PMA-differentiated cells, suggesting a distinct sensitivity between circulating monocytes and resident tissular macrophages. In addition, statins did not increase Oct-lipoprotein lipase binding activity that contains an Oct-1 binding element. The mRNA expression of interleukin-8, a chemokine containing Oct sites in its promoter, was diminished by statin pretreatment. Our results indicate that simvastatin and atorvastatin increase the activity of the transcriptional repressor Oct-1 in mononuclear cells, and could thus contribute to decrease the activation of these cells. These data suggest a possible novel mechanism supporting a certain anti-inflammatory effect of these two 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors.
authors.affiliation: Vascular Research Laboratory, Fundación Jiménez Díaz, Avda Reyes Católicos 2, 28040 Madrid, Spain. mortego@fjd.es
authors.forename: Mónica
authors.initials: M
authors.lastname: Ortego
authors.forename: Almudena Gómez
authors.initials: AG
authors.lastname: Hernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Bustos
authors.forename: Luis M
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Hernández-Presa
authors.forename: Jose
authors.initials: J
authors.lastname: Tuñón
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D000069059:Atorvastatin; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects* / Q000201:enzymology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006538:Heptanoic Acids / Q000494:pharmacology; D051863:Host Cell Factor C1; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D050811:Octamer Transcription Factor-1; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004268:DNA-Binding Proteins; C497692:HCFC1 protein, human; D006538:Heptanoic Acids; D051863:Host Cell Factor C1; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D050811:Octamer Transcription Factor-1; C494165:POU2F1 protein, human; D011758:Pyrroles; D014157:Transcription Factors; D000069059:Atorvastatin; D019821:Simvastatin