Cerivastatin, an inhibitor of HMG-CoA reductase, inhibits urokinase/urokinase-receptor expression and MMP-9 secretion by peripheral blood monocytes -A possible protective mechanism against atherothrombosis

It is now recognised that acute myocardial infarction results from the rupt ure of atherosclerotic plaques. Lymphocytes and macrophages, which infiltra te rupture sites, contribute to plaque degradation by expressing urokinase (u-PA) bound to cell membrane by urokinase receptor (u-PAR) and by secretin g metalloproteinase MMP-9. We have previously demonstrated that the uptake of oxidised LDL (ox-LDL) by monocytes induces an increase of u-PA and u-PAR expression. The present st udy shows that the expression of u-PA and u-PAR induced by ox-LDL on monocy te surface is suppressed by cerivastatin (a synthetic inhibitor of HMG-CoA reductase, Bayer) from 2 nM. This leads to reduced plasmin generation and m onocyte adhesion to vitronectin. Furthermore, higher concentrations of ceri vastatin (50-100 nM) reduce the expression of u-PA and u-PAR on unstimulate d monocytes. It also inhibits MMP-9 secretion but has no effect on TIMP-1 s ecretion, suggesting that the decrease in MMP-9 has a real protective effec t on plaque stabilisation. The inhibitory effect of cerivastatin on u-PA ex pression and MMP-9 secretion can be explained by the inhibition of NF-kappa B translocation into the nucleus, as shown by immunofluorescence. As farne syl-pyrophosphate reverses the effect of cerivastatin, it is postulated tha t these effects could also be due to the inhibition of Ras prenylation. Thi s was confirmed by confocal microscopy, which shows the Ras delocalisation from the monocyte membrane. The cerivastatin-induced effects on monocyte fu nctions could explain, at least in part, the protective effect of this drug against atherothrombotic events.