title: Fluvastatin increases the expression of adhesion molecules, monocyte chemoattractant protein-1 and tissue factor in HUVEC stimulated by patient IgG fractions containing antiphospholipid antibodies.
abstract: The presence of antiphospholipid antibodies (APLA) is associated with an increased risk of recurrent thrombosis and pregnancy loss. APLA are able to activate endothelial cells (EC) and induce an increase in the expression of inflammatory marker proteins, such as leukocyte adhesion molecules, tissue factor or the monocyte chemoattractant protein-1 (MCP-1). Our objective was to investigate the effect of statins on EC activation induced by APLA in vitro. IgG was purified from the plasma of six patients with APLA and from healthy controls. EC were incubated with patient IgG or with control IgG, in the presence or absence of 5microM of fluvastatin, and expression of the leukocyte adhesion molecules, VCAM-1 and E-selectin, analyzed by flow cytometry and by quantitative reverse transcriptase-PCR (QRT-PCR). The expression of tissue factor and the chemokine MCP-1 was analyzed by QRT-PCR alone. Incubation of EC with patient IgG increased the expression of VCAM-1, E-selectin, tissue factor and MCP-1. Prior treatment of the cells with fluvastatin further increased the expression of these proteins. The fluvastatin effect was reversed by co-incubation with mevalonate or geranylgeranylpyrophosphate and mimicked by the geranylgeranyl transferase inhibitor GGTI-286. Our results show that in cultured human EC, statins increase the extent of inflammatory activation induced by APLA. This effect appears to be mediated by an inhibitory effect of statins on one or more geranylgeranylated protein(s).
authors.affiliation: Unit of Haemostasis, University Hospital of Geneva, 24, Rue Micheli-du-Crest, 1211 Geneva 14, Switzerland, E-mail: philippe.demoerloose@hcuge.ch.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Dunoyer-Geindre
authors.forename: Yordanka
authors.initials: Y
authors.lastname: Dimitrova
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Fish
authors.forename: Nathalie
authors.initials: N
authors.lastname: Satta
authors.forename: Guido
authors.initials: G
authors.lastname: Reber
authors.forename: Egbert K O
authors.initials: EK
authors.lastname: Kruithof
authors.forename: Philippe
authors.initials: P
authors.lastname: de Moerloose
mesh_terms: D000293:Adolescent; D000328:Adult; D017152:Antibodies, Antiphospholipid / Q000494:pharmacology; D016736:Antiphospholipid Syndrome / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000187:drug effects / Q000235:genetics*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000032:analysis / Q000187:drug effects / Q000235:genetics*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000473:pathology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology; D008297:Male; D008875:Middle Aged; D013925:Thromboplastin / Q000032:analysis / Q000187:drug effects / Q000235:genetics*; D014470:Umbilical Cord / Q000166:cytology
chemical_list: D017152:Antibodies, Antiphospholipid; C111835:CCL2 protein, human; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; D005229:Fatty Acids, Monounsaturated; D007074:Immunoglobulin G; D007211:Indoles; D000077340:Fluvastatin; D013925:Thromboplastin