title: Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway.
abstract: C-reactive protein (CRP) is well-known inflammatory marker, and recognized as a risk predictor of pulmonary arterial diseases. Although statins have a beneficial effect in animal models and patients with pulmonary arterial hypertension (PAH), the underlying mechanisms of their actions have less been investigated. The aims of this study was to examined the effects of CRP on expressions of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), and the possible mechanisms of atorvastatin on CRP-induced IL-6 and MCP-1 production in cultured human pulmonary artery smooth muscle cells (PASMCs). In a preliminary study, the human PASMCs were stimulated by a variety of concentrations of CRP (5-200 microg/mL) at different time points (0, 3, 6, 9, 12, 18 and 24 h) for the purpose of determining the dose- and time-dependent effects of CRP on inflammatory response of the cells. Then, the cells were pre-incubated for 2 h with atorvastatin (0.1-10 micromol/L) in the presence of CRP. The supernatant levels of both IL-6 and MCP-1 secretion were examined by ELISA. The cellular mRNA expressions of IL-6 and MCP-1 and nuclear factor-kappaB (NF-kappaB) activity were determined by real-time reverse transcription and polymerase chain reaction (RT-PCR) and electrophoretic mobility shift assay (EMSA), respectively. CRP resulted in elevated IL-6 and MCP-1 secretion and mRNA expression in a dose- and time-dependent manner. In addition, CRP also significantly activated the NF-kappaB pathway. Preincubation with 0.1-10 micromol/L of atorvastatin significantly decreased the secretions of IL-6 and MCP-1 induced by CRP. Moreover, 10 micromol/L of atorvastatin completely abrogated CRP-induced increase in IL-6 and MCP-1 by attenuating the activation of NF-kappaB. The present study demonstrated that inhibiting effect of atorvastatin on CRP-induced inflammatory response in cultured PASMCs was associated with NF-kappaB pathway. This pathway might represent a promising target for controlling CRP-induced inflammatory response in pulmonary arterial diseases.
authors.affiliation: Department of Cardiology, Cardiovascular Institute & Fu Wai Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100037, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Jian-Jun
authors.initials: JJ
authors.lastname: Li
authors.forename: Jian-Guo
authors.initials: JG
authors.lastname: He
authors.forename: Jing-long
authors.initials: JL
authors.lastname: Nan
authors.forename: Yuan-lin
authors.initials: YL
authors.lastname: Guo
authors.forename: Chang-ming
authors.initials: CM
authors.lastname: Xiong
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002097:C-Reactive Protein / Q000378:metabolism*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D018836:Inflammation Mediators / Q000378:metabolism*; D015850:Interleukin-6 / Q000235:genetics; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000276:immunology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism*; D011651:Pulmonary Artery / Q000187:drug effects / Q000276:immunology; D011758:Pyrroles / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D018932:Chemokine CCL2; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018836:Inflammation Mediators; D015850:Interleukin-6; D016328:NF-kappa B; D011758:Pyrroles; D012333:RNA, Messenger; D002097:C-Reactive Protein; D000069059:Atorvastatin