title: Statins affect the presentation of endothelial chemokines by targeting to multivesicular bodies.
abstract: BACKGROUND
  In addition to lowering cholesterol, statins are thought to beneficially modulate inflammation. Several chemokines including CXCL1/growth-related oncogene (GRO)-α, CXCL8/interleukin (IL)-8 and CCL2/monocyte chemoattractant protein (MCP)-1 are important in the pathogenesis of atherosclerosis and can be influenced by statin-treatment. Recently, we observed that atorvastatin-treatment alters the intracellular content and subcellular distribution of GRO-α in cultured human umbilical vein endothelial cells (HUVECs). The objective of this study was to investigate the mechanisms involved in this phenomenon.
  
  
  RESULTS
  The effect of atorvastatin on secretion levels and subcellular distribution of GRO-α, IL-8 and MCP-1 in HUVECs activated by interleukin (IL)-1β were evaluated by ELISA, confocal microscopy and immunoelectron microscopy. Atorvastatin increased the intracellular contents of GRO-α, IL-8, and MCP-1 and induced colocalization with E-selectin in multivesicular bodies. This effect was prevented by adding the isoprenylation substrate GGPP, but not the cholesterol precursor squalene, indicating that atorvastatin exerts these effects by inhibiting isoprenylation rather than depleting the cells of cholesterol.
  
  
  CONCLUSIONS
  Atorvastatin targets inflammatory chemokines to the endocytic pathway and multivesicular bodies and may contribute to explain the anti-inflammatory effect of statins at the level of endothelial cell function.
authors: Division of Pathology, Oslo University Hospital, Oslo, Norway.
authors: Johanna
authors: J
authors: Hol
authors: Kari
authors: K
authors: Otterdal
authors: Unni M
authors: UM
authors: Breland
authors: Espen
authors: E
authors: Stang
authors: Turid M
authors: TM
authors: Pedersen
authors: Kathrine
authors: K
authors: Hagelsteen
authors: Trine
authors: T
authors: Ranheim
authors: Monika
authors: M
authors: Kasprzycka
authors: Bente
authors: B
authors: Halvorsen
authors: Guttorm
authors: G
authors: Haraldsen
authors: Pål
authors: P
authors: Aukrust
mesh_terms: D000069059:Atorvastatin; D002451:Cell Compartmentation / Q000187:drug effects; D054360:Chemokine CXCL1 / Q000378:metabolism; D018925:Chemokines / Q000378:metabolism*; D019040:E-Selectin / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology; D053583:Interleukin-1beta / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D057146:Multivesicular Bodies / Q000187:drug effects / Q000378:metabolism*; D017035:Pravastatin / Q000494:pharmacology; D054876:Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology; D012995:Solubility; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D060149:Tetraspanin 30 / Q000378:metabolism
chemical_list: D054360:Chemokine CXCL1; D018925:Chemokines; D019040:E-Selectin; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D053583:Interleukin-1beta; D011758:Pyrroles; D060149:Tetraspanin 30; D000077340:Fluvastatin; D000069059:Atorvastatin; D019821:Simvastatin; D017035:Pravastatin