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 (HMG-CoA) inhibitor, on the biosynthesis of tissue plasminogen activator (t-PA) and of its major physiological inhibitor (plasminogen activator inhibitor type 1, PAI-1) were investigated in cultured human umbilical vein endothelial cells (HUVEC). Fluvastatin (0.1 to 2.5 microM), 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 microg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor alpha (TNFalpha) or 0.1 microM phorbol myristate acetate (PMA). Mevalonate (100 microM), a precursor of isoprenoids, added to cells simultaneously with fluvastatin, suppressed the effect of the drug on PAI-1 both in unstimulated and stimulated cells as well as on t-PA antigen. Among intermediates of the isoprenoid pathway, all-transgeranylgeraniol (5 microM) but not farnesol (10 microM) prevented the effect of 2.5 microM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.
Mussoni
L
L
Institute of Pharmacological Sciences, University of Milan, Italy.
Banfi
C
C
Sironi
L
L
Arpaia
M
M
Tremoli
E
E
D002478:Cells, Cultured / Q000187:drug effects; D003864:Depression, Chemical; D004224:Diterpenes / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D005204:Farnesol / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000077340:Fluvastatin; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D012333:RNA, Messenger / Q000096:biosynthesis; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis* / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014471:Umbilical Veins
D004224:Diterpenes; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D008070:Lipopolysaccharides; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D005204:Farnesol; D000077340:Fluvastatin; C017338:geranylgeraniol; D010959:Tissue Plasminogen Activator; D013755:Tetradecanoylphorbol Acetate; D008798:Mevalonic Acid