Disturbed flow enhances inflammatory signaling and atherogenesis by increasing thioredoxin-1 level in endothelial cell nuclei.
Disturbed flow enhances inflammatory signaling and atherogenesis by increasing thioredoxin-1 level in endothelial cell nuclei.
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DOI：
10.1371/journal.pone.0108346
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Jones DP
中科院分区：
文献类型：
--
作者：
Go YM;Son DJ;Park H;Orr M;Hao L;Takabe W;Kumar S;Kang DW;Kim CW;Jo H;Jones DP
氧化应激伴随血流紊乱、炎症和心血管疾病(CVD)而发生，然而清除自由基的抗氧化剂对人类CVD的益处有限。硫氧还蛋白-1(Trx1)是一种硫醇抗氧化剂，通过控制蛋白质的硫醇/二硫键状态来保护其免受非自由基氧化剂的伤害；由于应激信号，Trx1可以从细胞质转移到细胞核，促进转录因子如核转录因子κB的结合，并增强炎症信号。核内Trx1的增加是否参与了致动脉粥样硬化的信号转导尚不清楚。体外和体内动脉粥样硬化模型被用来测试Trx1的核转位和相关的促炎信号。振荡切应力干扰流刺激内皮细胞Trx1核转位。在内皮细胞和转基因(TG)小鼠中，核Trx1的升高增强了干扰的血流刺激的促炎信号，包括NF-κB的激活和细胞黏附分子和细胞因子的表达增加。与野生型小鼠相比，核Trx1增加的TG小鼠由于血流紊乱而增加了颈动脉壁增厚，但在血脂或体重增加方面没有显着差异。颈动脉氧化还原蛋白质组学数据显示，扰动血流刺激蛋白质硫醇氧化，且TG小鼠的氧化程度高于野生型小鼠。Trx1从胞浆到胞核的转位在干扰的血流刺激的动脉粥样硬化形成中起着重要作用，它具有更大的胞浆蛋白氧化和增强的核转录因子活性。这些结果表明，抑制Trx1核转位的药物干预可能为预防炎症性疾病或进展提供一种新的方法。
Oxidative stress occurs with disturbed blood flow, inflammation and cardiovascular disease (CVD), yet free-radical scavenging antioxidants have shown limited benefit in human CVD. Thioredoxin-1 (Trx1) is a thiol antioxidant protecting against non-radical oxidants by controlling protein thiol/disulfide status; Trx1 translocates from cytoplasm to cell nuclei due to stress signaling, facilitates DNA binding of transcription factors, e.g., NF-κB, and potentiates inflammatory signaling. Whether increased nuclear Trx1 contributes to proatherogenic signaling is unknown. In vitro and in vivo atherogenic models were used to test for nuclear translocation of Trx1 and associated proinflammatory signaling. Disturbed flow by oscillatory shear stress stimulated Trx1 nuclear translocation in endothelial cells. Elevation of nuclear Trx1 in endothelial cells and transgenic (Tg) mice potentiated disturbed flow-stimulated proinflammatory signaling including NF-κB activation and increased expression of cell adhesion molecules and cytokines. Tg mice with increased nuclear Trx1 had increased carotid wall thickening due to disturbed flow but no significant differences in serum lipids or weight gain compared to wild type mice. Redox proteomics data of carotid arteries showed that disturbed flow stimulated protein thiol oxidation, and oxidation was higher in Tg mice than wild type mice. Translocation of Trx1 from cytoplasm to cell nuclei plays an important role in disturbed flow-stimulated proatherogenesis with greater cytoplasmic protein oxidation and an enhanced nuclear transcription factor activity. The results suggest that pharmacologic interventions to inhibit nuclear translocation of Trx1 may provide a new approach to prevent inflammatory diseases or progression.
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