Statins prevent endothelial cell activation induced by antiphospholipid (anti-β2-glycoprotein I) antibodies: Effect on the proadhesive and proinflammatory phenotype

Pier L. Meroni, Elena Raschi, Cinzia Testoni, Angela Tincani, Genesio Balestrieri, Raffaella Molteni, Munther A. Khamashta, Elena Tremoli, Marina Camera

Research output: Contribution to journalArticle

223 Citations (Scopus)

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-β2-glycoprotein I (anti-β2GPI) antibodies in vitro. Methods. Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule 1 (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 κB (NF-κB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-β2GPI antibodies, human recombinant IL-1β, tumor necrosis factor a, or lipopolysaccharide (LPS). Results. Fluvastatin reduced, in a concentration dependent manner (1-10 μM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-β2GPI 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-κB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-β2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 μM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. Conclusion. Endothelial activation mediated by anti-β2GPI 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.

Original languageEnglish
Pages (from-to)2870-2878
Number of pages9
JournalArthritis and Rheumatism
Volume44
Issue number12
DOIs
Publication statusPublished - 2001

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fluvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Glycoproteins
E-Selectin
Endothelial Cells
Phenotype
Antibodies
Antiphospholipid Syndrome
Human Umbilical Vein Endothelial Cells
Intercellular Adhesion Molecule-1
Lipopolysaccharides
Interleukin-6
Cytokines
Mevalonic Acid
Messenger RNA
Simvastatin
DNA
Interleukin-1
Monocytes
Oxidoreductases

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Statins prevent endothelial cell activation induced by antiphospholipid (anti-β2-glycoprotein I) antibodies : Effect on the proadhesive and proinflammatory phenotype. / Meroni, Pier L.; Raschi, Elena; Testoni, Cinzia; Tincani, Angela; Balestrieri, Genesio; Molteni, Raffaella; Khamashta, Munther A.; Tremoli, Elena; Camera, Marina.

In: Arthritis and Rheumatism, Vol. 44, No. 12, 2001, p. 2870-2878.

Research output: Contribution to journalArticle

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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-β2-glycoprotein I (anti-β2GPI) antibodies in vitro. Methods. Human umbilical vein endothelial cell (HUVEC) activation was evaluated as U937 monocyte adhesion, E-selectin, and intercellular adhesion molecule 1 (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 κB (NF-κB) DNA-binding activity was evaluated by the gel-shift assay. HUVECs were activated by polyclonal affinity-purified IgG, human monoclonal IgM anti-β2GPI antibodies, human recombinant IL-1β, tumor necrosis factor a, or lipopolysaccharide (LPS). Results. Fluvastatin reduced, in a concentration dependent manner (1-10 μM), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM-1 induced by anti-β2GPI 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-κB binding to DNA. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC exposed to anti-β2GPI antibodies or cytokines. Incubation of HUVECs with mevalonate (100 μM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. Conclusion. Endothelial activation mediated by anti-β2GPI 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.",
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AU - Meroni, Pier L.

AU - Raschi, Elena

AU - Testoni, Cinzia

AU - Tincani, Angela

AU - Balestrieri, Genesio

AU - Molteni, Raffaella

AU - Khamashta, Munther A.

AU - Tremoli, Elena

AU - Camera, Marina

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