The Study Of Effects Of Simvastatin On Production Of T-PA, PAI-1, SE-slectin, SICAM-1 In Endothelial Cells And The Mechanism

Objctives:To observe the influence of simvastatin on TNF- a induced production of Tissue-type plasminogen activator(t-PA) , plasminogen activator inhibitor-l(PAI-l), sE-selectin and soluble intercellular adhesion molecule-1 (sICAM-1) in human endothelial cells and to investigate the non-lipid mechanisms of simvastatin on anti-atherosclerosis.Methods:1. ECV304 cells were cultured in vitro.2. ECV304 cells were stimulated with TNF- a (0, 5, 10, 25 , 50 , 100 ng/ml) for 4, 18 or 24 hour .3. Simvastatin(0 , 0.1, 1.0, 10.0 mol/L) was used to incubate ECV304 cells for 4, 18 or 24 hour while stimulation with TNF- a (50 ng/ml).4. ECV304 cells were also co-incubated with TNF- a (50ng/ml) + simvastatin (10.0 mol/L) + mevalonate(0.2mmol/L) for 4, 18 or 24 hour.5. sE-selectin, sICAM-1 ,t-PA and PAI-1 in the supernatant were measured by enzyme linked immunosorbent assay(ELISA).Results:1. After stimulation of EC V3 04 cells with TNF- a ,the concentrationof t-PA in the supernatants had no significant changes compared with the control group and the concentration of PAI-K sE-selectin, sICAM-1 in the supernatants were higher than that of the control group.2. The addition of simvstatin of different concentrations to ECV304 cells in the presence of TNF- a (50ng/ml) decreased the production of PAI-K sE-selectin and sICAM-1 in the supernatants compared with the control group. Mevalonate could reversed the inhibitory effect of simvastatin on the production of PAI-1 , sE-selectin, sICAM-1 . The levels of t-PA had no statistically significant changes in all supernatant of cultivated cells.Conclusion:1. TNF- a could obviously induce the production of PAI-1, sE-selectin and sICAM-1 but had no significant influence on t-PA production.2. By inhibiting the production of PAI-1, sE-selectin and sICAM-1 induced by TNF- a , Simvastatin plays an essential role in keeping fibrinolytic balance and decreasing vascular inflammation independent of cholesterol-lowing effects.3. these pleiotropic effects of Simvastatin might be partly mediated by its inhibition on the mevalonate pathway.