146. Vastatins inhibit tissue factor in cultured human macrophages

We have examined the effect of fluvastatin, the first entirely synthetic 3-hydroxy-3-methylglutaryI coenzyme A reductase inhibitor structurally different from others, on the expression of tissue factor in human macrophages spontaneously differentiated in culture from blood monocytes. Fluvastatin decreased tissue factor activity in a dose-dependent manner (1-5 nmol/L) both in unstimulated and in LPSstimulated macrophages and this reduction paralleled the decrease in immunologically recognized tissue factor protein. The same results were obtained with another lipophilic vastatin, simvastatin, but not with the hydrophilic pravastatin. The reduction of tissue factor expression was observed also in macrophages enriched in cholesterol following exposure to acetyl-LDL (50 (ig/ml). The inhibitory effect of fluvastatin on tissue factor activity and antigen was fully reversible by coincubation with mevalonate (100 Hmol/L) or all-frvzs-geranylgeraniol (10 μmol/L), but not with dolichol, farnesol or geraniol. Tissue factor antigen and activity suppression were accompanied by a diminution in tissue factor mRNA levels, which was completely prevented by mevalonate. We conclude that lipophilic vastatins inhibit tissue factor expression in macrophages and as this effect is prevented by mevalonate and geranylgeraniol, a geranylgeranylated protein plays a crucial role in the regulation of tissue factor mRNA levels. The suppression of tissue factor in macrophages by vastatins indicates an additional mechanism by which these drugs interfere with the formation and progression of atherosclerotic plaque as well as thrombotic events in hyperlipidemic patients.