Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are able to reduce superoxide anion production by NADPH oxidase in THP-1-derived monocytes.
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.
D004305:Dose-Response Relationship, Drug; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009000:Monocytes / Q000187:drug effects* / Q000201:enzymology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013481:Superoxides / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000201:enzymology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013481:Superoxides; D006903:Hydroxymethylglutaryl CoA Reductases; D019255:NADPH Oxidases