氟伐他汀可抑制抗磷脂抗体对内皮细胞组织因子表达的上调作用。

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

作者信息

Ferrara D E, Swerlick R, Casper K, Meroni P L, Vega-Ostertag M E, Harris E N, Pierangeli S S

机构信息

Antiphospholipid Standardization Laboratory, Department of Microbiology, Biochemistry and Immunology, Morehouse School of Medicine, Atlanta, GA 30310-1495, USA.

出版信息

J Thromb Haemost. 2004 Sep;2(9):1558-63. doi: 10.1111/j.1538-7836.2004.00896.x.

DOI:10.1111/j.1538-7836.2004.00896.x

PMID:15333031

Abstract

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.

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.

摘要

背景

抗磷脂（aPL）抗体诱导血栓形成的机制包括上调内皮细胞（EC）上组织因子（TF）的表达。他汀类药物已被证明可降低肿瘤坏死因子（TNF-α）和脂多糖（LPS）诱导的EC上TF的水平。在最近的一项研究中，氟伐他汀在体内模型中抑制了aPL抗体的血栓形成和促炎特性。本研究的目的是确定氟伐他汀是否对aPL诱导的EC上TF的表达有影响。

方法

从4例抗磷脂综合征（APS）患者（IgG-APS）和对照血清（IgG-NHS）中纯化IgG。将培养的人脐静脉内皮细胞（HUVEC）用IgG-APS或IgG-NHS处理，或仅用培养基处理，或用佛波酯（PMA）作为阳性对照处理。在一些实验中，细胞在有和没有甲羟戊酸（100 μM）的情况下用氟伐他汀（2.5、5或10 μM）预处理。通过酶联免疫吸附测定（ELISA）测量HUVEC上TF的表达。

结果

PMA和四种IgG-APS制剂均以剂量依赖方式显著增加EC上TF的表达（分别为4.9倍、2.4倍、4.2倍、3.5倍和3.1倍）。氟伐他汀（10 μM）分别抑制PMA和四种IgG-APS对TF表达的作用达70%、47%、65%、22%和68%，且这种作用是剂量依赖性的。甲羟戊酸（100 μM）完全消除了氟伐他汀对aPL诱导的TF表达的抑制作用。