Department of Cardiology, Ren Ji Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, People's Republic of China.
J Cell Biochem. 2012 Feb;113(2):611-8. doi: 10.1002/jcb.23388.
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.
巨噬细胞与氧化型低密度脂蛋白（oxLDL）相互作用，在动脉粥样硬化斑块的起始、进展和随后的稳定性中起着关键作用。他汀类药物是 3-羟基-3-甲基戊二酰辅酶 A（HMG CoA）还原酶的抑制剂，除了降低血脂作用外，还能降低炎症蛋白的表达。然而，oxLDL 诱导的巨噬细胞中他汀类药物的作用及其详细的抗炎机制尚不清楚。在本研究中，我们研究了阿托伐他汀对 oxLDL 刺激的小鼠巨噬细胞炎症反应的影响，并分析了其潜在机制。通过实时 PCR 测定肿瘤坏死因子（TNF）α和单核细胞趋化蛋白-1（MCP-1）mRNA 水平。通过实时 PCR 和 Western blot 检测环氧化酶-2（COX-2）的表达。通过 Western blot 测定丝裂原活化蛋白激酶（MAPK）磷酸化和 IκBα降解。我们的结果表明，oxLDL 暴露会显著改变 RAW264.7 细胞的形态，并增加 TNFα和 MCP-1 的分泌。而阿托伐他汀预处理以剂量依赖性方式显著抑制 oxLDL 诱导的形态改变和炎症细胞因子表达。进一步的分子机制研究表明，oxLDL 以时间依赖性方式上调 COX-2 的转录和蛋白表达。然而，阿托伐他汀预处理抑制 COX-2 表达、MAPK 激活和 IκBα降解。因此，我们得出结论，阿托伐他汀的抗炎作用是通过抑制促炎 COX-2 介导的。此外，抑制 ERK 磷酸化和 IκBα降解参与了这种调节。我们的研究结果提供了新的证据，表明他汀类药物通过抑制炎症而不仅仅是降低胆固醇来抑制炎症反应，从而发挥其抗动脉粥样硬化作用。
