SummaryThe 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.

SummaryOxidative modification of LDL, which dysregulates the homeostasis between blood and vascular cells, and alterations of endothelial function are considered among the early events in the pathogenesis of atherosclerosis. This study was designed to evaluate the impact of progressive LDL oxidation on the thrombotic response both in vitro and in vivo, and to address the potential effect of antioxidants. Tissue factor was induced by progressive LDL oxidation in HUVEC, and this event was in parallel to the appearance of the apoptotic phenotype. Both these phenomena were mediated by ERK1/2 activation and were prevented by LDL pre-enrichment with antioxidants. In contrast, antioxidants failed to affect tPA and PAI-1 secretion, which was increased by LDL, either native or oxidized. Tissue factor-pathway inhibitor was also increased upon HUVEC exposure to progressively oxidized LDL. LDL, in the presence of an oxidative agent, trigger a thrombogenic response in vivo, mostly TF-dependent, in an in situ model of platelet deposition. This effect was markedly attenuated when LDL were enriched with antioxidants. It can be concluded that vascular thrombogenicity is induced by progressive LDL oxidation and that alterations of the antioxidant/oxidant balance of the LDL particle in favor of the antioxidant tone are protective against the thrombotic response triggered by oxidative stress. The extrapolation of these data in a clinical setting, even if not easy, offers potential insights for the use of antioxidants in the prevention of thrombotic complications associated with atherothrombosis.

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