title: Statins prevent endothelial cell activation induced by antiphospholipid (anti-beta2-glycoprotein I) antibodies: effect on the proadhesive and proinflammatory phenotype.
abstract: OBJECTIVE
  To investigate the ability of statins, the inhibitors of the hydroxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta2-glycoprotein I (anti-beta2GPI) antibodies in vitro.
  
  
  METHODS
  Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule I (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection assay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-beta2GPI antibodies, human recombinant IL-1beta, tumor necrosis factor alpha, or lipopolysaccharide (LPS).
  
  
  RESULTS
  Fluvastatin reduced, in a concentration-dependent manner (1-10 microM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-beta2GPI antibodies as well as by cytokines or LPS. Another lipophilic statin, simvastatin, displayed similar effects but to a lesser extent than fluvastatin. The inhibition of E-selectin expression exerted by fluvastatin was related to the impairment of NF-kappaB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-beta2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 microM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin.
  
  
  CONCLUSIONS
  Endothelial activation mediated by anti-beta2GPI antibody can be inhibited by statins. Because of the suggested role of endothelial cell activation in the pathogenesis of antiphospholipid syndrome (APS), our data provide, for the first time, a rationale for using statins as an additional therapeutic tool in APS.
authors.affiliation: IRCCS Istituto Auxologico Italiano, Milan, Italy. pierluigi.meroni@unimi.it
authors.forename: P L
authors.initials: PL
authors.lastname: Meroni
authors.forename: E
authors.initials: E
authors.lastname: Raschi
authors.forename: C
authors.initials: C
authors.lastname: Testoni
authors.forename: A
authors.initials: A
authors.lastname: Tincani
authors.forename: G
authors.initials: G
authors.lastname: Balestrieri
authors.forename: R
authors.initials: R
authors.lastname: Molteni
authors.forename: M A
authors.initials: MA
authors.lastname: Khamashta
authors.forename: E
authors.initials: E
authors.lastname: Tremoli
authors.forename: M
authors.initials: M
authors.lastname: Camera
mesh_terms: D017152:Antibodies, Antiphospholipid / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology; D002478:Cells, Cultured; D019040:E-Selectin / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D006023:Glycoproteins / Q000276:immunology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000494:pharmacology; D007075:Immunoglobulin M / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D012333:RNA, Messenger / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D020298:U937 Cells; D014471:Umbilical Veins / Q000166:cytology; D053482:beta 2-Glycoprotein I
chemical_list: D017152:Antibodies, Antiphospholipid; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D019040:E-Selectin; D005229:Fatty Acids, Monounsaturated; D006023:Glycoproteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007211:Indoles; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D053482:beta 2-Glycoprotein I; D018799:Intercellular Adhesion Molecule-1; D000077340:Fluvastatin