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3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells.
Arterioscler Thromb Vasc Biol. 2002 Nov 01; 22(11):1784-9.AT

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 (1 to 10 micromol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximately 50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 micromol/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-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.

Authors+Show Affiliations

Department of Cardiovascular Physiology, University of Goettingen, Goettingen, Germany.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12426205

Citation

Wagner, Andreas H., et al. "3-hydroxy-3-methylglutaryl Coenzyme a Reductase-independent Inhibition of CD40 Expression By Atorvastatin in Human Endothelial Cells." Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 22, no. 11, 2002, pp. 1784-9.
Wagner AH, Gebauer M, Güldenzoph B, et al. 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells. Arterioscler Thromb Vasc Biol. 2002;22(11):1784-9.
Wagner, A. H., Gebauer, M., Güldenzoph, B., & Hecker, M. (2002). 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells. Arteriosclerosis, Thrombosis, and Vascular Biology, 22(11), 1784-9.
Wagner AH, et al. 3-hydroxy-3-methylglutaryl Coenzyme a Reductase-independent Inhibition of CD40 Expression By Atorvastatin in Human Endothelial Cells. Arterioscler Thromb Vasc Biol. 2002 Nov 1;22(11):1784-9. PubMed PMID: 12426205.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 3-hydroxy-3-methylglutaryl coenzyme A reductase-independent inhibition of CD40 expression by atorvastatin in human endothelial cells. AU - Wagner,Andreas H, AU - Gebauer,Matthias, AU - Güldenzoph,Björn, AU - Hecker,Markus, PY - 2002/11/12/pubmed PY - 2002/12/5/medline PY - 2002/11/12/entrez SP - 1784 EP - 9 JF - Arteriosclerosis, thrombosis, and vascular biology JO - Arterioscler. Thromb. Vasc. Biol. VL - 22 IS - 11 N2 - 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 micromol/L) inhibited interferon-gamma plus tumor necrosis factor-alpha-stimulated CD40 expression by approximately 50%, an effect that was not reversed by the HMG-CoA reductase product mevalonic acid (400 micromol/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-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. SN - 1524-4636 UR - https://www.unboundmedicine.com/medline/citation/12426205/3_hydroxy_3_methylglutaryl_coenzyme_A_reductase_independent_inhibition_of_CD40_expression_by_atorvastatin_in_human_endothelial_cells_ L2 - http://www.ahajournals.org/doi/full/10.1161/01.atv.0000037098.20829.31?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -