期刊
JOURNAL OF CELLULAR BIOCHEMISTRY
卷 113, 期 2, 页码 611-618出版社
WILEY
DOI: 10.1002/jcb.23388
关键词
ATORVASTATIN; COX-2; oxLDL; MACROPHAGES; ATHEROSCLEROSIS
资金
- National Natural Science Foundation of China [81070239, 30971185]
- Shanghai Municipal Natural Science Foundation [09JC1409400, 10JC1409400, 11ZR1421600]
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)a 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 I?Ba degradation were determined by Western blotting. Our results showed that exposure of RAW264.7cells to oxLDL, substantially changed the morphology of the cells and increased TNFa 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 IBa 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 I?Ba 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. J. Cell. Biochem. 113: 611618, 2012. (C) 2011 Wiley Periodicals, Inc.
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