Effect of atorvastatin and fluvastatin on the expression of plasminogen activator inhibitor type-1 in cultured human endothelial cells.
Inhibitors of HMG-CoA reductase, namely statins, improve endothelial function independently of their cholesterol-lowering effects. Plasminogen activator inhibitor type-1 (PAI-1) plays a critical role in vascular pathophysiology both at the intra- and extravascular levels. We therefore investigated the effects of atorvastatin (ATOR) and fluvastatin (FLU) on PAI-1 and also tissue-type plasminogen activator (t-PA) synthesis in 20% fetal calf serum-cultured human umbilical vein endothelial cells (HUVEC) stimulated or not by recombinant human pro-inflammatory cytokines, i.e. tumor necrosis factor alpha (TNFalpha) and interleukin 1alpha (IL-1alpha). In non-stimulated HUVEC, ATOR and FLU significantly diminished (-50% at 2.0 micromol/l) the constitutive production of PAI-1 (mRNA level and protein secretion). This effect was prevented by addition of mevalonate (100 micromol/l). In HUVEC cultivated in 20% fetal calf serum, the t-PA antigen accumulation was not significantly altered, whereas in low serum concentration (1%) a significant stimulatory effect of ATOR (+30%) and FLU (+76%) was observed. In TNFalpha-stimulated cells, ATOR and FLU had a modest down-modulating effect (-17 and -20%, respectively) on TNFalpha-induced increase in PAI-1 synthesis. No effect of statins was observed in IL-1alpha-stimulated HUVEC, suggesting that statins do not interfere with the up-regulation of PAI-1 synthesis by pro-inflammatory cytokines. However, ATOR and FLU inhibited the TNFalpha-induced decrease in t-PA release. In conclusion, these results show that statins favorably modulate the expression of fibrinolytic factors produced by human endothelial cells.
Lopez
S
S
INSERM EPI 99-36 and Université de la Méditerranée, Laboratoire d'Hématologie, Faculté de Médecine, 27 Bd. Jean Moulin, 13385 Cedex 5, Marseille, France.
Peiretti
F
F
Bonardo
B
B
Juhan-Vague
I
I
Nalbone
G
G
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D000069059:Atorvastatin; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism*; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D000077340:Fluvastatin; D006538:Heptanoic Acids / Q000494:pharmacology*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D007375:Interleukin-1 / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D011758:Pyrroles / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D010959:Tissue Plasminogen Activator / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D000924:Anticholesteremic Agents; D005229:Fatty Acids, Monounsaturated; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D007375:Interleukin-1; D017395:Plasminogen Activator Inhibitor 1; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D000077340:Fluvastatin; D000069059:Atorvastatin; D010959:Tissue Plasminogen Activator