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

Luciana Mussoni, Cristina Banfi, Luigi Sironi, Magda Arpaia, Elena Tremoli

Research output: Contribution to journalArticlepeer-review

Abstract

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 μM), 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 μg/ml bacterial lipopolysaccharide (LPS), 100 U/ml tumour necrosis factor α (TNFα) or 0.1 μM phorbol myristate acetate (PMA). Mevalonate (100 μM), 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-trans-geranylgeraniol (5 μM) but not farnesol (10 μM) prevented the effect of 2.5 μM fluvastatin on PAI-1 antigen, which suggests that the former intermediate of the isoprenoid synthesis is responsible for the observed effects.

Original languageEnglish
Pages (from-to)59-64
Number of pages6
JournalThrombosis and Haemostasis
Volume84
Issue number1
Publication statusPublished - 2000

Keywords

  • 3-Hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitor
  • Endothelial cells
  • Isoprenoids
  • Plasminogen activator

ASJC Scopus subject areas

  • Hematology

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