Statins suppress THP-1 cell migration and secretion of matrix metalloproteinase 9 by inhibiting geranylgeranylation

Macrophages secrete matrix metalloproteinase 9 (MMP-9), an enzyme that weak ens the fibrous cap of atherosclerotic plaques, predisposing them to placqu e rupture and subsequent ischemic events. Recent work indicates that statin s strongly reduce the possibility of heart attacck. Furthermore, these comp ounds appear to exert beneficial effects not only by lowering plasma low-de nsity-lipoprotein cholesterol but also by directly affecting the artery wal l. To evaluate whether statins influence the proinflammatory responses of m onocytic cells, we studied their effects on the chemotactic migration and M MP-9 secretion of human monocytic cell line THP-1. Simvastatin dose depende ntly inhibited THP-1 cell migration mediated by monocyte chemoattractant pr otein 1, with a 50% inhibitory concentration of about 50 nM, It also inhibi ted bacterial lipopolysaccharide-stimulated secretion of MMP-9, The effects of simvastatin were completely reversed by mevalonate and its derivatives, farnesylpyrophosphate and geranylgeranyl pyrophosphate, but not by ubiquin one. Additional studies revealed similar but more profound inhibitory effec ts with L-839,867, a specific inhibitor of geranylgeranyl transferase. Howe ver, alpha -hydroxyfarnesyl phosphonic acid, an inhibitor of farnesyl trans ferase, had no effect, C3 exoenzyme, a specific inhibitor of the prenylated small signaling Rho proteins, mimicked the inhibitory effects of simvastat in and L-839,867. These data supported the role of,geranylgeranylation in t he migration and MMP-9 secretion of monocytes.