Vastatins Inhibit Tissue Factor in Cultured Human Macrophages

Arteriosclerosis, Thrombosis, and Vascular Biology - Tập 17 Số 2 - Trang 265-272 - 1997
S. Colli1, Sonia Eligini2, Mariagrazia Lalli3, Marina Camera4, Rodolfo Paoletti5, Elena Tremoli6
1Susanna Colli the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
2Sonia Eligini the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
3Mariagrazia Lalli the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
4Marina Camera the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
5Rodolfo Paoletti the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy
6Elena Tremoli the E. Grossi Paoletti Center, Institute of Pharmacological Sciences, University of Milan, Milan, Italy

Tóm tắt

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 κB 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.

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Arteriosclerosis, Thrombosis, and Vascular Biology

Tập 17 Số 2

265-272

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