Statins prevent endothelial cell activation induced by antiphospholipid (anti-?2-glycoprotein I) antibodies: Effect on the proadhesive and proinflammatory phenotype

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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 α, 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, display 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.