Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor, Kruppel-like factor 2.
OBJECTIVE
Statins have beneficial vascular effects beyond their cholesterol-lowering action. Since macrophages play a central role in atherogenesis, we characterized the effects of simvastatin on gene expression profile of human peripheral blood monocyte (HPBM)-macrophages.


RESULTS
Gene expression profile was studied using Affymetrix gene chip analysis. Lentiviral gene transfer of Kruppel-like factor 2 (KLF-2) was used to further study its role in macrophages. Simvastatin treatment lead to downregulation of many pro-inflammatory genes including several chemokines [e.g. monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory proteins-1alpha and beta, interleukin-2 receptor-beta], members of the tumour necrosis factor family (e.g. lymphotoxin beta), vascular cell adhesion molecule-1, and tissue factor (TF). Simvastatin also modulated the expression of several transcription factors essential for inflammation: NF-kappaB relA/p65 subunit and ets-1 were downregulated, and an atheroprotective transcription factor KLF-2 was upregulated. The effects of simvastatin on MCP-1 and TF could be mimicked by KLF-2 overexpression using lentiviral gene transfer.


CONCLUSIONS
Simvastatin has a strong anti-inflammatory effect on HPBM cells including upregulation of the atheroprotective factor KLF-2. This may partly explain the beneficial effects of statins on cardiovascular diseases.
Tuomisto
Tiina T
TT
Department of Biotechnology and Molecular Medicine, A I Virtanen Institute, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland.
Lumivuori
Henri
H
Kansanen
Emilia
E
Häkkinen
Sanna-Kaisa
SK
Turunen
Mikko P
MP
van Thienen
Johannes V
JV
Horrevoets
Anton J
AJ
Levonen
Anna-Liisa
AL
Ylä-Herttuala
Seppo
S
D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling / Q000379:methods; D018014:Gene Transfer Techniques; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D017368:Protein Prenylation; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D013925:Thromboplastin / Q000378:metabolism; D013997:Time Factors; D051996:Transcription Factor RelA / Q000378:metabolism; D048069:Tumor Necrosis Factors / Q000378:metabolism; D015854:Up-Regulation
D000893:Anti-Inflammatory Agents; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; D050783:Proto-Oncogene Proteins c-ets; C498143:RELA protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D048069:Tumor Necrosis Factors; D013925:Thromboplastin; D019821:Simvastatin