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 functi on independently of their cholesterol-lowering effects. Plasminogen activat or inhibitor type-1 (PAI-1) plays a critical role in vascular pathophysiolo gy both at the intra- and extravascular levels. We therefore investigated t he effects of atorvastatin (ATOR) and fluvastatin (FLU) on PAI-1 and also t issue-type plasminogen activator (t-PA) synthesis in 20% fetal calf serum-c ultured human umbilical vein endothelial cells (HUVEC) stimulated or not by recombinant human pro-inflammatory cytokines, i.e. tumor necrosis factor a lpha (TNF alpha) and interleukin 1 alpha (IL-1 alpha). In non-stimulated HU VEC, ATOR and FLU significantly diminished (-50% at 2.0 mu mol/l) the const itutive production of PAI-1 (mRNA level and protein secretion). This effect was prevented by addition of mevalonate (100 mu mol/l). In HUVEC cultivate d in 20% fetal calf serum, the t-PA antigen accumulation was not significan tly altered, whereas in low serum concentration (1%) a significant stimulat ory effect of ATOR (+30%) and FLU (+76%) was observed. In TNF alpha-stimula led cells. ATOR and FLU had a modest down-modulating effect (-17 and - 20%, respectively) on TNF alpha-induced increase in PAI-1 synthesis. No effect of statins was observed in IL-1 alpha-stimulated HUVEC, suggesting that sta tins do not interfere with the up-regulation of PAI-1 synthesis by pro-infl ammatory cytokines. However, ATOR and FLU inhibited the TNF alpha-induced d ecrease in t-PA release. In conclusion, these results show that statins fav orably modulate the expression of fibrinolytic factors produced by human en dothelial cells. (C) 2000 Elsevier Science Ireland Ltd. All rights reserved .