on September 12, 2002
Published online before print September 12, 2002, doi: 10.1161/01.ATV.0000037098.20829.31
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Submitted on June 26, 2002
Accepted on August 21, 2002
3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase-Independent Inhibition of CD40 Expression by Atorvastatin in Human Endothelial Cells
Andreas H. Wagner ;
From the Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany.
* To whom correspondence should be addressed. E-mail: hecker{at}veg-physiol.med.uni-goettingen.de.
Objective—3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) exert potent anti-inflammatory effects that are independent of their cholesterol-lowering action. We have investigated the effects of these drugs on cytokine-stimulated CD40 expression in human cultured endothelial cells and monocytes.
Methods and Results—Reverse transcription-polymerase chain reaction and Western blot analysis revealed that treatment of either cell type with atorvastatin, cerivastatin, or pravastatin (1 to 10 µmol/L) inhibited interferon-
plus tumor necrosis factor-
-stimulated CD40 expression by 
50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 µmol/L). In contrast, mevalonic acid prevented the inhibitory effect of atorvastatin on cytokine-stimulated vascular cell adhesion molecule-1 expression and subsequent adhesion of THP-1 monocytes to the cultured endothelial cells. Transcription factor analysis revealed an inhibition by atorvastatin of nuclear factor-
B plus signal transducer and activator of transcription-1-dependent de novo synthesis of interferon regulatory factor-1, governing cytokine-stimulated CD40 expression in these cells. One consequence of this statin-dependent downregulation of CD40 expression was a decrease in CD40 ligand-induced endothelial interleukin-12 expression.
Conclusions—By interfering with cytokine-stimulated CD40 expression in vascular cells, statins thus seem capable of attenuating CD40 ligand-induced proinflammatory responses, including atherosclerosis. In addition, they point to the coexistence of HMG-CoA reductase-dependent and -independent effects of statins in the same cell type.
Key words: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors • endothelial cells • atherosclerosis • CD40 • interleukin-12 • gene expression
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