title: Simvastatin modulates chemokine and chemokine receptor expression by geranylgeranyl isoprenoid pathway in human endothelial cells and macrophages.
abstract: OBJECTIVE
  Atherosclerosis is a chronic immuno-inflammatory disease involving the recruitment of monocytes and T lymphocytes to the vascular wall of arteries. Chemokines and their receptors, known to induce leukocyte migration, have recently been implicated in atherogenesis. Recent in vitro and in vivo studies have suggested that statins (3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors) have anti-inflammatory properties beyond their lipid-lowering effects. Thus, the aim of the present study was to investigate whether simvastatin reduces the expression of chemokines and chemokine receptors in two major cell types implicated in atherogenesis and to test isoprenoid intermediates involved in their regulation.
  
  
  RESULTS
  We performed in vitro experiments on human vascular endothelial cells and human primary macrophages. First, we have shown by ELISA that 1 microM simvastatin significantly reduced MCP-1 in endothelial cells (ECs) and macrophages stimulated with TNF-alpha or IFN-gamma, respectively. Messenger RNA analysis revealed that expression of the chemokines MCP-1, MIP-1alpha and MIP-1beta, as well as the chemokine receptors CCR1, CCR2, CCR4 and CCR5, was decreased by simvastatin, both in ECs and macrophages. Furthermore, the statin effects were reversed by mevalonate and mimicked by the geranylgeranyl transferase inhibitor (GGTI), whereas the farnesyl transeferase inhibitor (FTI) had no effect. These results suggests that statins act via inhibition of the geranylgeranylation of proteins.
  
  
  CONCLUSIONS
  Our results demonstrate that statins reduce chemokine and chemokine receptor expressions in human ECs and macrophages via inhibition of the geranylgeranylpyrophosphate pathway. Thus, our data provide further evidence that statins have anti-inflammatory properties beyond their lipid-lowering effects. These findings highlight specific novel therapeutic targets for cardiovascular diseases to reduce inflammation mediated by chemokines and their receptors.
authors.affiliation: Cardiology Division, Department of Medicine, Geneva University Hospital, Foundation for Medical Research, 64 Avenue Roseraie, 1211 Geneva, Switzerland.
authors.forename: Niels R
authors.initials: NR
authors.lastname: Veillard
authors.forename: Vincent
authors.initials: V
authors.lastname: Braunersreuther
authors.forename: Claire
authors.initials: C
authors.lastname: Arnaud
authors.forename: Fabienne
authors.initials: F
authors.lastname: Burger
authors.forename: Graziano
authors.initials: G
authors.lastname: Pelli
authors.forename: Sabine
authors.initials: S
authors.lastname: Steffens
authors.forename: François
authors.initials: F
authors.lastname: Mach
mesh_terms: D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects* / Q000378:metabolism; D011106:Polyisoprenyl Phosphates / Q000378:metabolism; D017368:Protein Prenylation / Q000187:drug effects; D012333:RNA, Messenger / Q000032:analysis / Q000037:antagonists & inhibitors; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D019821:Simvastatin / Q000494:pharmacology*; D013729:Terpenes / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D018925:Chemokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019402:Macrophage Inflammatory Proteins; D011106:Polyisoprenyl Phosphates; D012333:RNA, Messenger; D019707:Receptors, Chemokine; D013729:Terpenes; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate