Fluvastatin inhibits up‐regulation of tissue factor expression by antiphospholipid antibodies on endothelial cells

Abstract

Summary. 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-a) 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 lM) with and without mevalonate (100 lM). 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 lM) 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 dosedependent. Mevalonate (100 lM) completely abrogated the inhibitory effects of fluvastatin on TF expression induced by aPL. Conclusion: 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.

Thrombin Binding Predicts the Effects of Sequence Changes in a Human Monoclonal Antiphospholipid Antibody on Its In Vivo Biologic Actions

“…It is surprising that none of the IS4 variants enhanced expression of tissue factor on the cultured HUVECs because numerous previous studies have demonstrated aPL mediated up-regulation of tissue factor from HUVECs (15,16,41). Furthermore, enhanced tissue factor expression is thought to be a major mechanism of thrombosis in patients with APS.…”

“…Previous studies have shown aPL to activate cultured HUVECs leading to up-regulation of E-selectin, ICAM-1, VCAM-1, and tissue factor (15,16). Using in vivo models of microcirculation, aPL have been shown to increase leukocyte adherence to EC and enhance thrombus formation (17).…”

Statins as antiinflammatory and immunomodulatory agents: A future in rheumatologic therapy?

“…In separate studies, fluvastatin has been shown to decrease leukocyte-endothelial adhesion in postcapillary venules (135). Fluvastatin also significantly decreases expression of tissue factor by HUVECs exposed to human antiphospholipid antibodies (136).…”

Antiphospholipid syndrome: long-time research on pathogenic mechanisms has finally lead to new therapeutic strategies

“…Additionally, several classical drugs, such as statins and hydroxychloroquine, can have antithrombotic effects through these mechanisms of action [13,14].…”