on October 24, 2002
Arteriosclerosis, Thrombosis, and Vascular Biology. 2002
Published online before print October 24, 2002, doi: 10.1161/01.ATV.0000043456.48735.20
Published online before print October 24, 2002, doi: 10.1161/01.ATV.0000043456.48735.20
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Submitted on May 19, 2002
Accepted on August 23, 2002
HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells
Wolfgang Dichtl *;
From the Department of Internal Medicine (W.D., M.F., H.F.A., S.P.S., O.P., F.W.), Division of Cardiology, Leopold-Franzens-University Innsbruck, Austria; Wallenberg Laboratory (W.D., M.P.S.A., J.N.), Department of Medicine, Malmö University Hospital, Lund University, Sweden; and Department of Cell Biochemistry (J.D.), Institute of Molecular Biology and Biotechnology, Jagiellonian University, Krakow, Poland.
* To whom correspondence should be addressed. E-mail: wolfgang.dichtl{at}uibk.ac.at.
Objective—Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation.
Methods and Results—Simvastatin, atorvastatin, and lovastatin (0.1 to 10 µmol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-
B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-B or AP-1-dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated IB-
protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells.
Conclusions—HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-B, AP-1, and hypoxia-inducible factor-1. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.
Key words: statins • nuclear factor-
B •
activator protein-1 •
hypoxia-inducible factor-1 •
vascular endothelial growth factor
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