Hilgendorff A, Muth H, Parviz B, Staubitz A, Haberbosch W, Tillmanns H, Hölschermann H
Department of Internal Medicine, Justus Liebig University, Giessen, Germany.
Int J Clin Pharmacol Ther. 2003 Sep;41(9):397-401. doi: 10.5414/cpp41397.
The benefits of statin therapy in cardiovascular medicine are ascribed to its lipid-lowering effect as well as its anti-inflammatory properties. Whereas all statins have been shown to reduce cholesterol plasma levels, their effect on inflammatory markers has been inconsistent. Here, we show that statins differ markedly in their effectiveness in preventing activation of NF-kappaB, a transcription factor involved in the activation of immediately early genes during inflammation.
Six statins (atorvastatin (Atv), cerivastatin (Cer), fluvastatin (Flu), lovastatin (Lov), pravastatin (Pra), simvastatin (Sim)) were tested for their ability to influence the induction of NF-kappaB in human monocytes (Mo) during inflammation. Mo isolated from healthy blood donors were incubated with LPS (10 microg/ml) in the presence and absence of statin (0.001-5 microM). NF-kappaB binding activity (EMSA), degradation and phosphorylation of the inhibitor protein IkappaB-alpha (Western blotting), tissue factor (TF) mRNA (rtPCR), and TF activity (clotting assay) were analyzed.
All statins inhibited LPS-induced NF-kappaB binding activity in Mo in a dose-dependent manner. The inhibitory effect was due to reduced phosphorylation and degradation of the NF-kappaB inhibitor protein IkappaB, and was primarily dependent on the absence of mevalonate. Whilst this effect appeared with all statins, there were marked differences in the degree of inhibition between the statins. Cer (45 +/- 9% inhibition, p < 0.05) was 9-fold more effective in reducing NF-kappaB activation than Flu (5 +/- 10% inhibition). The differences in the potency of statins (Cer > Atv > Sim > Pra > Lov > Flu) were also reflected at the transcriptional level and the protein level of NF-kappaB controlled tissue factor expression.
The finding that statins differ in their potency in interfering with the activation of NF-kappaB signaling in human monocytes further supports the hypothesis that some statins inhibit the inflammatory response more than others.
他汀类药物在心血管医学中的益处归因于其降脂作用以及抗炎特性。虽然所有他汀类药物均已显示可降低血浆胆固醇水平，但其对炎症标志物的影响并不一致。在此，我们表明他汀类药物在预防核因子κB（NF-κB）激活方面的有效性存在显著差异，NF-κB是一种在炎症过程中参与立即早期基因激活的转录因子。
测试了六种他汀类药物（阿托伐他汀（Atv）、西立伐他汀（Cer）、氟伐他汀（Flu）、洛伐他汀（Lov）、普伐他汀（Pra）、辛伐他汀（Sim））在炎症期间影响人单核细胞（Mo）中NF-κB诱导的能力。从健康献血者分离的Mo在有和没有他汀类药物（0.001 - 5 microM）的情况下与脂多糖（LPS，10微克/毫升）一起孵育。分析了NF-κB结合活性（电泳迁移率变动分析）、抑制蛋白IκB-α的降解和磷酸化（蛋白质印迹法）、组织因子（TF）mRNA（逆转录聚合酶链反应）以及TF活性（凝血测定）。
所有他汀类药物均以剂量依赖性方式抑制Mo中LPS诱导的NF-κB结合活性。抑制作用归因于NF-κB抑制蛋白IκB的磷酸化和降解减少，并且主要取决于甲羟戊酸的缺乏。虽然所有他汀类药物都有这种作用，但他汀类药物之间的抑制程度存在显著差异。西立伐他汀（45±9%抑制，p < 0.05）在降低NF-κB激活方面比氟伐他汀（5±10%抑制）有效9倍。他汀类药物效力的差异（西立伐他汀 > 阿托伐他汀 > 辛伐他汀 > 普伐他汀 > 洛伐他汀 > 氟伐他汀）也反映在NF-κB控制的组织因子表达的转录水平和蛋白质水平上。
他汀类药物在干扰人单核细胞中NF-κB信号激活的效力方面存在差异这一发现进一步支持了以下假设，即某些他汀类药物比其他药物更能抑制炎症反应。
