3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase-Independent Inhibition of CD40 Expression by Atorvastatin in Human Endothelial Cells

Abstract

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 (I to 10 mumol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximate to50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 mumol/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-kappaB plus signal transducer and activator of transcription-I-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.