Statins, 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors, Are Able to Reduce Superoxide Anion Production by NADPH Oxidase in THP-1-Derived Monocytes

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Abstract
Reactive oxygen species formation by phagocytes and subsequent modifications of vascular wall are involved in the early step of human atherogenesis. This study looked for the effect of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors on NADPH oxidase–dependent superoxide anion production in THP-1 cells, a monocyte-derived cell line, and on the translocation of p21 Rac 2 and p67phox. A 30-min incubation with simvastatin (50 μM) inhibited phorbol 12-myristate 13-acetate–induced superoxide anion production by monocytes (32%) and a maximum inhibition was obtained at 3 h of incubation (69.5%). In addition, after 3 h of incubation a dose-dependent inhibition was obtained in the range 10–50 μM of simvastatin with a median inhibitory concentration of 36 ± 2.3 μM. Mevalonic acid (100 and 300 μM) and geranylgeraniol (100 μM) totally prevented the simvastatin-induced inhibitory effect of superoxide production by monocytes whereas farnesyl PP (100 μM) partially prevented (50%) this effect. In addition, simvastatin inhibited the translocation of p21 rac 2 and p67phox, suggesting that geranylgeranylation is required for NADPH oxidase activation. In another set of experiments, the rank order of potency of different statins on NADPH oxidase was determined (pravastatin