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Cardiovascular Research Advance Access [Accepted Manuscript] published online on January 10, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn007
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Simvastatin has an anti-inflammatory effect on macrophages via upregulation of an atheroprotective transcription factor KLF-2

Tiina T. Tuomisto1,*, Henri Lumivuori1,*, Emilia Kansanen1, Sanna-Kaisa Häkkinen1, Mikko P. Turunen1, Johannes V. van Thienen2, Anton J. Horrevoets2, Anna-Liisa Levonen1 and Seppo Ylä-Herttuala1,3,4,

1 Department of Biotechnology and Molecular Medicine, A. I. Virtanen Institute, Kuopio University, Kuopio, Finland
2 Department of Medical Biochemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3 Department of Medicine, Kuopio University, Kuopio, Finland
4 Gene Therapy Unit, Kuopio University Hospital, Kuopio, Finland

Address for correspondence and reprint requests: Seppo Ylä-Herttuala, M.D., Ph.D, FESC Department of Molecular Medicine, A. I. Virtanen Institute University of Kuopio P.O. Box 1627, FIN-70211 Kuopio Finland Phone: +358-17-162075, Fax: +358-17-163751 E-mail: Seppo.Ylaherttuala{at}uku.fi

Aim: 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-macrophages (HPBM).

Methods: 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.

Results: Simvastatin treatment lead to downregulation of many proinflammatory genes including several chemokines (e.g. monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory proteins-1{alpha} and β, interleukin-2 receptor-β), members of the tumor necrosis factor family (TNF) (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-{kappa}B 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 including upregulation of the atheroprotective factor KLF-2. This may partly explain the beneficial effects of statins on cardiovascular diseases.

Time for primary review: 27

* Authors with equal contribution


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