Fluvastatin inhibits up-regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells.
BACKGROUND
Mechanisms of thrombosis induced by antiphospholipid (aPL) antibodies include up-regulation of tissue factor (TF) expression on endothelial cells (ECs). Statins have been shown to reduce levels of TF induced by tumor necrosis factor (TNF-alpha) and lipopolysaccharide (LPS) on ECs. In a recent study, fluvastatin inhibited thrombogenic and proinflammatory properties of aPL antibodies in in vivo models. The aim of this study was to determine whether fluvastatin has an effect on aPL-induced expression of TF on ECs.


METHODS
IgGs were purified from four patients with APS (IgG-APS) and from control sera (IgG-NHS). Cultured human umbilical vein endothelial cells (HUVEC) were treated with IgG-APS or IgG-NHS or with medium alone or with phorbol myristate acetate (PMA), as a positive control. In some experiments, cells were pretreated with fluvastatin (2.5, 5 or 10 micro m) with and without mevalonate (100 micro m). TF expression on HUVECs was measured by ELISA.


RESULTS
PMA and the four IgG-APS preparations increased the expression of TF on EC significantly (4.9-, 2.4-, 4.2-, 3.5- and 3.1-fold, respectively), in a dose-dependent fashion. Fluvastatin (10 micro m) inhibited the effects of PMA and the four IgG-APS on TF expression by 70, 47, 65, 22 and 68%, respectively, and this effect was dose-dependent. Mevalonate (100 micro m) completely abrogated the inhibitory effects of fluvastatin on TF expression induced by aPL.


CONCLUSIONS
Because of the suggested pathogenic role of aPL on induction of TF on ECs, our data provide a rationale for using statins as a therapeutic tool in treatment of thrombosis in APS.
Ferrara
D E
DE
Antiphospholipid Standardization Laboratory, Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310-1495, USA.
Swerlick
R
R
Casper
K
K
Meroni
P L
PL
Vega-Ostertag
M E
ME
Harris
E N
EN
Pierangeli
S S
SS
D000328:Adult; D017152:Antibodies, Antiphospholipid / Q000008:administration & dosage*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology*; D005260:Female; D000077340:Fluvastatin; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D008875:Middle Aged; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
D017152:Antibodies, Antiphospholipid; D005229:Fatty Acids, Monounsaturated; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007211:Indoles; D000077340:Fluvastatin; D013925:Thromboplastin; D008798:Mevalonic Acid