BACKGROUND: Chlamydia pneumoniae stimulates chronic inflammation in vascular cells. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may have an ameliorating effect. We investigated possible mechanisms. METHODS AND 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.
BACKGROUND: Chlamydia pneumoniae stimulates chronic inflammation in vascular cells. Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) may have an ameliorating effect. We investigated possible mechanisms. METHODS AND RESULTS: We infected human macrophages that in coculture spread infection to vascular smooth muscle cells (VSMCs). Cerivastatin (250 nmol/L) reduced VSMCinfection by 33%. Western blotting made it apparent that VSMCinfection 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: Jan Rupp; Thomas Hellwig-Burgel; Viola Wobbe; Ulrike Seitzer; Ernst Brandt; Matthias Maass Journal: Proc Natl Acad Sci U S A Date: 2005-02-18 Impact factor: 11.205
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Authors: Leena Erkkilä; Matti Jauhiainen; Kirsi Laitinen; Kristiina Haasio; Terttu Tiirola; Pekka Saikku; Maija Leinonen Journal: Antimicrob Agents Chemother Date: 2005-09 Impact factor: 5.191