Schmidt Wolfgang M, Spiel Alexander O, Jilma Bernd, Wolzt Michael, Müller Markus
Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria.
Pharmacogenet Genomics. 2008 Feb;18(2):109-20. doi: 10.1097/FPC.0b013e3282f44d81.
To gain insight into molecular mechanisms of anti-inflammatory effects of statins, we have studied global gene expression in circulating leucocytes in an in-vivo model of acute inflammation following statin administration.
For this purpose, a randomized, double-blind, placebo-controlled, crossover study was conducted in six healthy male volunteers, who received simvastatin (80 mg/day), rosuvastatin (40 mg/day) or placebo before infusion of E. coli lipopolysaccharide (LPS). Leucocyte RNA isolated before and after statin treatment, and after LPS-infusion was subjected to GeneChip transcript profiling (n=42).
Data analysis revealed that statins exert little effect on leucocyte gene expression. Statin-responsive genes included several immune response genes and the cholesterol efflux transporter (ABCA1). Rosuvastatin appeared to moderately downregulate expression of the genes encoding the inflammatory response proteins orosomucoid (ORM1) and interleukin 18 receptor accessory protein (IL18RAP). LPS-infusion induced a pronounced response of the leucocyte transcriptome, notably affecting transcripts related to immune regulation, cell proliferation and motility. While the majority of LPS-induced changes were not modulated by either statin, few select genes responded differently after statin treatment, such as the genes encoding the CD32 receptor (FCGR2A) or the protein geranylgeranyltransferase 1b subunit (PGGT1B).
We found that few 'inflammatory' genes appeared to be moderately down regulated during rosuvastatin administration, such as the ORM1 or IL18RAP genes. The small number of statin-induced differences, both during treatment and after LPS-induced inflammation, however, suggests that statins might exert their anti-inflammatory action mainly at the posttranscriptional level rather than at the level of gene transcription.
为深入了解他汀类药物抗炎作用的分子机制，我们在他汀类药物给药后的急性炎症体内模型中研究了循环白细胞中的全局基因表达。
为此，对6名健康男性志愿者进行了一项随机、双盲、安慰剂对照的交叉研究，这些志愿者在输注大肠杆菌脂多糖（LPS）之前接受了辛伐他汀（80毫克/天）、瑞舒伐他汀（40毫克/天）或安慰剂。在他汀类药物治疗前后以及LPS输注后分离的白细胞RNA进行基因芯片转录谱分析（n = 42）。
数据分析显示他汀类药物对白细胞基因表达影响很小。他汀类药物反应性基因包括几个免疫反应基因和胆固醇流出转运蛋白（ABCA1）。瑞舒伐他汀似乎适度下调了编码炎症反应蛋白类粘蛋白（ORM1）和白细胞介素18受体辅助蛋白（IL18RAP）的基因表达。LPS输注诱导了白细胞转录组的明显反应，显著影响了与免疫调节、细胞增殖和运动相关的转录本。虽然大多数LPS诱导的变化未被任何一种他汀类药物调节，但少数特定基因在他汀类药物治疗后反应不同，例如编码CD32受体（FCGR2A）或蛋白质香叶基香叶基转移酶1b亚基（PGGT1B）的基因。
我们发现，在服用瑞舒伐他汀期间，少数“炎症”基因似乎受到适度下调，如ORM1或IL18RAP基因。然而，在治疗期间和LPS诱导的炎症后，他汀类药物诱导的差异数量较少，这表明他汀类药物可能主要在转录后水平而非基因转录水平发挥其抗炎作用。
