title: Hydroxymethylglutaryl coenzyme A reductase inhibition reduces Chlamydia pneumoniae-induced cell interaction and activation.
abstract: BACKGROUND
  Chlamydia pneumoniae stimulates chronic inflammation in vascular cells. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may have an ameliorating effect. We investigated possible mechanisms.
  
  
  RESULTS
  We infected human macrophages that in coculture spread infection to vascular smooth muscle cells (VSMCs). Cerivastatin (250 nmol/L) reduced VSMC infection by 33%. Western blotting made it apparent that VSMC infection resulted in increased cell membrane-associated RhoA and Rac1, implying increased prenylation of these proteins. This effect was blocked by statin but circumvented by mevalonate. Cytochrome C assays showed that infected VSMCs produced increased reactive oxygen species that was blocked by statin. Infection increased nuclear transcription factor-kappaB expression in VSMCs that was dose-dependently suppressed by statin. Infected VSMCs produced and released RANTES and MCP-1. Statin dose-dependently blocked this production both at the mRNA and protein levels. Mevalonate and M geranylgeranylpyrophosphate circumvented these effects.
  
  
  CONCLUSIONS
  C pneumoniae can be transmitted from macrophages to VSMCs. VSMCs showed an activation profile typical of atherosclerosis, namely Rac1 and RhoA prenylation, nuclear transcription factor-kappaB activation, reactive oxygen species production, and chemokine production. Statin reduces macrophage-mediated C pneumoniae-induced signaling and transmission.
authors.affiliation: Franz Volhard Clinic at the Max Delbrück Center for Molecular Medicine, HELIOS Klinikum-Berlin, Wiltberg Strasse 50, 13125 Berlin, Germany. dechend@fvk-berlin.de
authors.forename: Ralf
authors.initials: R
authors.lastname: Dechend
authors.forename: Jens
authors.initials: J
authors.lastname: Gieffers
authors.forename: Rainer
authors.initials: R
authors.lastname: Dietz
authors.forename: Achim
authors.initials: A
authors.lastname: Joerres
authors.forename: Jan
authors.initials: J
authors.lastname: Rupp
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Matthias
authors.initials: M
authors.lastname: Maass
mesh_terms: D000818:Animals; D001161:Arteriosclerosis / Q000382:microbiology; D000069059:Atorvastatin; D002450:Cell Communication / Q000187:drug effects; D002462:Cell Membrane / Q000737:chemistry / Q000201:enzymology; D002478:Cells, Cultured; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D023521:Chlamydophila Infections / Q000188:drug therapy* / Q000201:enzymology* / Q000635:transmission; D016993:Chlamydophila pneumoniae / Q000201:enzymology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008264:Macrophages / Q000201:enzymology / Q000382:microbiology; D051379:Mice; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000201:enzymology / Q000382:microbiology; D016328:NF-kappa B / Q000378:metabolism; D017368:Protein Prenylation; D011725:Pyridines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
chemical_list: D018925:Chemokines; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011725:Pyridines; D011758:Pyrroles; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000069059:Atorvastatin; C086276:cerivastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein