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

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 p67. A 30-min incubation with simvastatin (50 micro M ) 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 micro M of simvastatin with a median inhibitory concentration of 36 +/- 2.3 micro M Mevalonic acid (100 and 300 micro M ) and geranylgeraniol (100 micro M ) totally prevented the simvastatin-induced inhibitory effect of superoxide production by monocytes whereas farnesyl PP (100 micro M ) partially prevented (50%) this effect. In addition, simvastatin inhibited the translocation of p21 rac 2 and p67, 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 < cerivastatin < lovastatin < fluvastatin < simvastatin). In conclusion, inhibition of superoxide formation by HMG CoA reductase inhibitors is highly suitable to prevent or limit the oxidative stress involved in the atherosclerosis process.