In-vivo Effects of Simvastatin and Rosuvastatin on Global Gene Expression in Peripheral Blood Leucocytes in a Human Inflammation Model

Objective: 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.

Methods: 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).

Results: 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).

Conclusion: 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.