The synthesis of mevalonate by HMG-CoA reductase is a key event in the biosynthesis of isoprenoids, which are essential for normal cellular proliferation and activity. 1 2 3 These drugs appear to reduce plaque progression in coronary and carotid arteries 4 5 and prevent restenosis in experimental animals 6 7 and humans, 8 perhaps by influencing the behavior of smooth muscle or endothelial cells 9 10 11 12 and in particular by blocking the biosynthesis of mevalonate. HMG-CoA reductase inhibitors (vastatins) are widely used to suppress plasma LDL cholesterol levels in patients with primary hypercholesterolemia. 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. 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. 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. Suppression of TF antigen and activity was accompanied by a diminution in TF mRNA levels, which was completely prevented by mevalonate. 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. The reduction in TF expression was also observed in macrophages enriched in cholesterol after exposure to 50 μg/mL acetylated low density lipoprotein. The same results were obtained with another lipophilic vastatin, simvastatin, but not with hydrophilic pravastatin. 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. 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. ![]() Customer Service and Ordering Information.Stroke: Vascular and Interventional Neurology.Journal of the American Heart Association (JAHA).Circ: Cardiovascular Quality & Outcomes. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |