Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress-induced cell injury
Naturally occurring free thiols within β2-glycoprotein I in vivo: nitrosylation, redox modification by endothelial cells, and regulation of oxidative stress-induced cell injury
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DOI：
10.1182/blood-2009-04-215335
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发表时间：
2010-09-16
期刊：
影响因子：
20.3
通讯作者：
Krilis, Steven A.
中科院分区：
文献类型：
--
作者：
Ioannou, Yiannis;Zhang, Jing-Yun;Krilis, Steven A.
β 2-糖蛋白I （β 2GPI）是一种进化保守的、丰富的循环蛋白。尽管其功能仍不确定，但积累的证据表明其与内皮细胞和凝血系统的组成部分相互作用，表明其在血管生物学中具有调节作用。我们的研究小组已经证明，硫氧还蛋白1 （TRX-1）在β 2GPI中产生游离硫醇，这一过程可能对血小板粘附具有调节作用。该报告扩展了这些研究，并首次在多种人类和小鼠血清样本中证明了β - 2GPI与游离硫醇的存在。为了探索血管表面如何调节β 2GPI的氧化还原状态，未受刺激的人内皮细胞和EAhy926细胞被证明能够放大β 2GPI中游离硫醇生成的影响。内皮细胞表面除蛋白二硫异构酶外，还分泌多种氧化还原酶，如内质网蛋白46 （ERp 46）和TRX-1还原酶。此外，β - 2GPI中生成的一种或多种游离硫醇也被证明是亚硝基化的。最后，通过显示含游离硫醇的β 2GPI在保护内皮细胞和EAhy926细胞免受氧化应激诱导的细胞死亡方面具有强大的作用，探讨了这些发现的功能意义。（Blood. 2010; 116(11): 1961-1970）
beta 2-Glycoprotein I (beta 2GPI) is an evolutionary conserved, abundant circulating protein. Although its function remains uncertain, accumulated evidence points toward interactions with endothelial cells and components of the coagulation system, suggesting a regulatory role in vascular biology. Our group has shown that thioredoxin 1 (TRX-1) generates free thiols in beta 2GPI, a process that may have a regulatory role in platelet adhesion. This report extends these studies and shows for the first time evidence of beta 2GPI with free thiols in vivo in both multiple human and murine serum samples. To explore how the vascular surface may modulate the redox status of beta 2GPI, unstimulated human endothelial cells and EAhy926 cells are shown to be capable of amplifying the effect of free thiol generation within beta 2GPI. Multiple oxidoreductase enzymes, such as endoplasmic reticulum protein 46 (ERp 46) and TRX-1 reductase, in addition to protein disulfide isomerase are secreted on the surface of endothelial cells. Furthermore, one or more of these generated free thiols within beta 2GPI are also shown to be nitrosylated. Finally, the functional significance of these findings is explored, by showing that free thiol-containing beta 2GPI has a powerful effect in protecting endothelial cells and EAhy926 cells from oxidative stress-induced cell death. (Blood. 2010; 116(11): 1961-1970)