Fluvastatin inhibits basal and stimulated plasminogen activator inhibitor 1, but induces tissue type plasminogen activator in cultured human endothelial cells

The effects of fluvastatin, a synthetic hydroxymethylglutaryl coenzyme A (H MG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator it-P A and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothel ial cells (HUVEC). Fluvastatin (0.1 to 2.5 mu M), concentration-dependently reduced the release of PAI-1 antigen by unstimulated HUVEC, subsequent to a reduction in PAI-1 steady-state mRNA levels and de novo protein synthesis . In contrast, it increased t-PA secretion. The drug also reduced PAI-1 antigen secreted in response to 10 mu g/ml bact erial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor a (TNF alph a) or 0.1 mu M phorbol myristate acetate (PMA). Mevalonate (100 mu M), a precursor of isoprenoids, added to cells simultane ously with fluvastatin, suppressed the effect of the drug on PAI-I both in unstimulated and stimulated cells as well as on t-PA antigen. Among interme diates of the isoprenoid pathway, all-trans-geranylgeraniol (5 mu M) but no t farnesol (10 mu M) prevented the effect of 2.5 mu M fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synt hesis is responsible for the observed effects.