title: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors decrease Fas ligand expression and cytotoxicity in activated human T lymphocytes.
abstract: BACKGROUND
  HMG-CoA reductase inhibitors reduce cardiovascular mortality, although the mechanisms of action have not been completely elucidated. The presence of T cells and apoptotic cells in atherosclerotic plaques is well established, the reduction of cellular content being a marker of their vulnerability. One of the main mechanisms of cell death activation is the Fas-Fas ligand (FasL) system.
  
  
  RESULTS
  We studied whether HMG-CoA reductase inhibitors can regulate FasL expression and cytotoxicity in human T cells (Jurkat cells). Activation of Jurkat cells with phorbol esters and ionomycin increased FasL expression, an effect prevented by atorvastatin or simvastatin. Mevalonate and geranylgeranylpyrophosphate but not farnesylpyrophosphate prevented the effect of atorvastatin, indicating that protein geranylation was involved in FasL expression. The C3 exotoxin, which selectively inactivates Rho proteins, also decreased FasL expression on T cells. Overexpression of constitutively active RhoA increased FasL expression in Jurkat cells, and dominant-negative RhoA decreased FasL expression in activated cells, indicating that RhoA is implicated in FasL expression. Atorvastatin also decreased cytotoxic activity of activated Jurkat cells on FasL-sensitive cells. Finally, atorvastatin treatment reduced FasL expression in peripheral blood mononuclear cells and human carotid atherosclerotic plaques.
  
  
  CONCLUSIONS
  Atorvastatin regulates FasL expression in T cells, probably because of the inhibition of RhoA prenylation. These results provide novel information by which atorvastatin may regulate the cytotoxic activity of T cells and the number of cells in the atherosclerotic plaque.
authors.affiliation: Vascular Research Laboratory, Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.
authors.forename: Luis Miguel
authors.initials: LM
authors.lastname: Blanco-Colio
authors.forename: Begoña
authors.initials: B
authors.lastname: Muñoz-García
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Martín-Ventura
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.forename: Cristina
authors.initials: C
authors.lastname: Díaz
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Hernández
authors.forename: Jesús
authors.initials: J
authors.lastname: Egido
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology; D000818:Animals; D000069059:Atorvastatin; D001905:Botulinum Toxins / Q000494:pharmacology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005799:Genes, Dominant; D006538:Heptanoic Acids / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects* / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008798:Mevalonic Acid / Q000494:pharmacology; D051379:Mice; D010703:Phorbol Esters / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011758:Pyrroles / Q000037:antagonists & inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019821:Simvastatin / Q000494:pharmacology; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection; D020742:rhoA GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007476:Ionophores; D008562:Membrane Glycoproteins; D010703:Phorbol Esters; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; D036002:ADP Ribose Transferases; C063007:exoenzyme C3, Clostridium botulinum; D001905:Botulinum Toxins; D020742:rhoA GTP-Binding Protein; D008798:Mevalonic Acid