Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:265-272
© 1997 American Heart Association, Inc.
Articles |
Vastatins Inhibit Tissue Factor in Cultured Human Macrophages
A Novel Mechanism of Protection Against Atherothrombosis
the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
Correspondence to Prof Elena Tremoli, Institute of Pharmacological Sciences, University of Milan, Via Balzaretti 9, 20133 Milan, Italy. E-mail tremoli@isfunix.farma.unimi.it.
We examined the effect of fluvastatin, the first entirely synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor that is structurally different from other vastatins, on tissue factor (TF) expression in human macrophages spontaneously differentiated in culture from blood monocytes. Fluvastatin decreased TF activity in a dose-dependent manner (1 to 5 µmol/L) in both unstimulated and lipopolysaccharide-stimulated macrophages, and this reduction paralleled the decrease in immunologically recognized TF protein. The same results were obtained with another lipophilic vastatin, simvastatin, but not with hydrophilic pravastatin. The reduction in TF expression was also observed in macrophages enriched in cholesterol after exposure to 50 µg/mL acetylated low density lipoprotein. The inhibitory effect of fluvastatin on TF activity and antigen was fully reversible by coincubation with 100 µmol/L mevalonate or 10 µmol/L all-trans-geranylgeraniol but not with dolichol, farnesol, or geraniol. Suppression of TF antigen and activity was accompanied by a diminution in TF mRNA levels, which was completely prevented by mevalonate. Furthermore, fluvastatin impaired bacterial lipopolysaccharide–induced binding of c-Rel/p65 heterodimers to a 
B site in the TF promoter, indicating that this drug influences induction of the TF gene. We conclude that lipophilic vastatins inhibit TF expression in macrophages, and because this effect is prevented by mevalonate and geranylgeraniol, a geranylgeranylated protein plays a crucial role in the regulation of TF biosynthesis. The suppression of TF in macrophages by vastatins indicates a potential mechanism by which these drugs interfere with the formation and progression of atherosclerotic plaque as well as thrombotic events in hyperlipidemic patients.
Key Words: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors • procoagulant activity • isoprenoids • atherosclerosis • thrombosis
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