Fluvastatin (Sandoz, Basel) is a newly developed synthetic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which effectively reduces cholesterol levels in hypercholesterolemic patients, has been shown to affect also several cellular functions, (i.e. cell growth, chemotaxis, IL-8 release, tissue factor expression). In this study we have examined the effects of Fluvastatin on the secretion of plasminogen activator inhibitor type-1 (PAI-1) in cultured human endothelial cells (HUVEC). Confluent HUVEC were incubated for 24 hours with medium containing 15% PCS and Fluvastatin (0.1-2.5μmol/L). Cells were then challenged with LPS (10 μg/ml) or PMA (100 nM) for further 16 hours in the presence of Fluvastatin and 2.5% FCS. Fluvastatin decreased PAI-1 antigen release in a dose-dependent manner both in unstimulated and LPS or PMA stimulated cells. The effect of Fluvastatin was more pronounced in cells stimulated with PMA than with LPS. At the highest concentration used, (2.5μmol/), Fluvastatin reduced the secretion of PAI-1 by 84% in unstimulated cells and by 32% and 67% in LPS and PMA stimulated cells respectively. The inhibitory effect of Fluvastatin on PAI-1 antigen was fully reversible by coincubation with mevalonate (100μmol/L) or all-frans-geranylgeraniol (10μmol/L) but not by farnesol. These data indicate that Fluvastatin, besides its effect on plasma lipids, mediates the reduction in PAI-1 antigen levels, a "marker" of endothelial cells dysfunction, throughout the inhibition of mevalonate biosynthesis.
|Number of pages||1|
|Issue number||SUPPL. 3|
|Publication status||Published - 1996|
ASJC Scopus subject areas