title: Effect of atorvastatin on adhesive phenotype of human endothelial cells activated by tumor necrosis factor alpha.
abstract: We studied the effect of atorvastatin on the adhesive phenotype of human endothelial cells (HUVEC) stimulated by tumor necrosis factor (TNF)-alpha. Surface expression of adhesion molecules on HUVEC was examined by flow cytometry and confocal microscopy, and adhesion of monocytes (human THP-1 cell line) was measured in vitro under flow conditions. In TNF-alpha-activated HUVEC, atorvastatin significantly enhanced surface expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, E-selectin, and fractalkine, when compared with TNF-alpha stimulation alone. This enhancement was reversed by mevalonate or geranylgeranyl pyrophosphate (GGPP) and was mimicked by an inhibitor of geranylgeranylation. The enhancing effect of atorvastatin was restricted to TNF-alpha-inducible adhesion molecule and was the reflect of an increased protein synthesis (mRNA and protein) and not of a reduced shedding. Confocal microscopy examination showed that atorvastatin also altered the surface distribution of adhesion molecules. Adhesion of human THP-1 cells on TNF-alpha-activated HUVEC was significantly reduced by atorvastatin (-42% at 1 microM). Mevalonate or GGPP restored the TNF-alpha-induced adhesive potential. These results show that atorvastatin, by inhibiting prenylation of G proteins, enhances the TNF-alpha-induced expression of adhesion molecules at the endothelial cell surface and also alters their surface distribution which may account for the reduced binding of monocytes.
authors.affiliation: Faculté de Médecine Timone, Marseille, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Bernot
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Benoliel
authors.forename: Franck
authors.initials: F
authors.lastname: Peiretti
authors.forename: Sophie
authors.initials: S
authors.lastname: Lopez
authors.forename: Bernadette
authors.initials: B
authors.lastname: Bonardo
authors.forename: Pierre
authors.initials: P
authors.lastname: Bongrand
authors.forename: Irène
authors.initials: I
authors.lastname: Juhan-Vague
authors.forename: Gilles
authors.initials: G
authors.lastname: Nalbone
mesh_terms: D000069059:Atorvastatin; D002460:Cell Line; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018922:HL-60 Cells; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis*; D010641:Phenotype; D011758:Pyrroles / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014471:Umbilical Veins / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis*
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D000069059:Atorvastatin