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

Objective. To investigate the ability of statins, the inhibitors of the hyd roxymethylglutaryl-coenzyme A reductase enzyme, to affect endothelial cell activation induced by anti-beta (2)-glycoprotein I (anti-beta (2)GPI) antib odies in vitro. Methods. Human umbilical vein endothelial cell (HUVEC) activation was evalu ated as U937 monocyte adhesion, E-selectin, and intercellular adhesion mole cule 1 (ICAM-1) expression by cell enzyme-linked immunosorbent assay and as interleukin-6 (IL-6) messenger RNA (mRNA) expression by RNA protection ass ay. E-selectin-specific nuclear factor kappaB (NF-kappaB) DNA-binding activ ity was evaluated by the gel-shift assay. HUVECs were activated by polyclon al affinity-purified IgG, human monoclonal IgM anti-beta (2)GPI antibodies, human recombinant IL-1 beta, tumor necrosis factor alpha, or lipopolysacch aride (LPS). Results. Fluvastatin reduced, in a concentration-dependent manner (1-10 muM ), the adhesion of U937 to HUVECs and the expression of E-selectin and ICAM -1 induced by anti-beta (2)GPI antibodies as well as by cytokines or LPS. A nother lipophilic statin, simvastatin, displayed similar effects but to a l esser extent than fluvastatin. The inhibition of E-selectin expression exer ted by fluvastatin was related to the impairment of NF-kappaB binding to DN A. Moreover, the drug attenuated the expression of IL-6 mRNA in HUVEC expos ed to anti-beta (2)GPI antibodies or cytokines. Incubation of HUVECs with m evalonate (100 muM), concomitantly with fluvastatin, greatly prevented the inhibitory effect of statin. Conclusion. Endothelial activation mediated by anti-beta (2)GPI antibody ca n be inhibited by statins. Because of the suggested role of endothelial cel l activation in the pathogenesis of antiphospholipid syndrome (APS), our da ta provide, for the first time, a rationale for using statins as an additio nal therapeutic tool in APS.