title: Atorvastatin suppresses inflammatory response induced by oxLDL through inhibition of ERK phosphorylation, IκBα degradation, and COX-2 expression in murine macrophages.
abstract: Macrophages crosstalk with oxidized low-density lipoprotein (oxLDL), play a critical role in the initiation, progression, and subsequently stability of atherosclerotic plaques. Statins, inhibitors of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase, reduce the expression of inflammatory proteins in addition to their lipid-lowering action. However, the effect and detailed anti-inflammation mechanisms of statins in macrophages induced by oxLDL remain unclearly. In the present study, we investigated the effect of atorvastatin on inflammatory response upon oxLDL stimulation in murine macrophages and analyzed the underlying mechanisms. Tumor necrosis factor (TNF)α and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were assayed by real-time PCR. The expression of cyclooxygenases-2 (COX-2) was detected by real-time PCR and Western blotting. While mitogen-activated protein kinase (MAPK) phosphorylation and IκBα degradation were determined by Western blotting. Our results showed that exposure of RAW264.7 cells to oxLDL, substantially changed the morphology of the cells and increased TNFα and MCP-1 secretion. While pretreatment with atorvastatin resulted in a significant inhibition of oxLDL-induced morphological alteration and inflammatory cytokines expression in a dose-dependent fashion. Further investigation of the molecular mechanism revealed that oxLDL upregulated the transcription and protein expression of COX-2 in a time-dependent manner. Whereas, pretreatment with atorvastatin suppressed COX-2 expression, MAPK activation and IκBα degradation. Thus, we conclude that the anti-inflammatory effect of atorvastatin is mediated through the inhibition of proinflammatory COX-2. Furthermore, suppression of ERK phosphorylation and IκBα degradation is involved in this regulation. Our findings provide a novel evidence that statins suppress inflammatory response, exert its anti-atherogenic actions via against inflammation beyond cholesterol-lowing effect.
authors.affiliation: Department of Cardiology, Ren Ji Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, People's Republic of China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Shao
authors.forename: Ling-Hong
authors.initials: LH
authors.lastname: Shen
authors.forename: Liu-Hua
authors.initials: LH
authors.lastname: Hu
authors.forename: Jun
authors.initials: J
authors.lastname: Pu
authors.forename: Qing
authors.initials: Q
authors.lastname: Jing
authors.forename: Ben
authors.initials: B
authors.lastname: He
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002460:Cell Line; D048430:Cell Shape; D018925:Chemokines / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006538:Heptanoic Acids / Q000494:pharmacology*; D020672:I-kappa B Proteins / Q000378:metabolism*; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D008077:Lipoproteins, LDL; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D059748:Proteolysis / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: D000893:Anti-Inflammatory Agents; D018925:Chemokines; D006538:Heptanoic Acids; D020672:I-kappa B Proteins; D008077:Lipoproteins, LDL; C000606205:Nfkbia protein, mouse; D011758:Pyrroles; C099252:oxidized low density lipoprotein; D000072000:NF-KappaB Inhibitor alpha; D000069059:Atorvastatin; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3