Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy.
Novel anti-thrombotic agent for modulation of protein disulfide isomerase family member ERp57 for prophylactic therapy.
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用于调节蛋白质二硫键异构酶家族成员 ERp57 进行预防性治疗的新型抗血栓剂
DOI：
10.1038/srep10353
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发表时间：
2015-06-03
影响因子：
4.6
通讯作者：
Lee SM
中科院分区：
文献类型：
--
作者：
Cui G;Shan L;Guo L;Chu IK;Li G;Quan Q;Zhao Y;Chong CM;Zhang Z;Yu P;Hoi MP;Sun Y;Wang Y;Lee SM
蛋白质二硫键异构酶(PDI)家族成员，包括PDI和ERp57，成为抗血栓治疗的新靶点，但具有选择性的化学制剂仍有待探索。我们先前报道了一种新的丹参素(DSS)的衍生物，被称为ADTM，在体外和体内对氧化应激诱导的细胞损伤和急性心肌梗死显示出强大的心脏保护作用。在这里，我们利用化学蛋白质组学的方法，确定ERp57是ADTM的主要靶点。ADTM对ERp57的氧化还原活性有明显的抑制作用，抑制二磷酸腺苷诱导的P-选择素和αIIbβ3整合素的表达，并阻断ERp57与αIIbβ3的相互作用。此外，在体外，ADTM还能抑制花生四烯酸(AA)诱导的和腺苷二磷酸诱导的血小板聚集。此外，ADTM还能显著抑制体内大鼠的血小板聚集和血栓形成。综上所述，ADTM代表了以ERp57为靶点的抗血栓治疗的有前景的候选药物。
Protein disulfide isomerase (PDI) family members including PDI and ERp57 emerge as novel targets for anti-thrombotic treatments, but chemical agents with selectivity remain to be explored. We previously reported a novel derivative of danshensu (DSS), known as ADTM, displayed strong cardioprotective effects against oxidative stress-induced cellular injuryin vitroand acute myocardial infarctin vivo. Herein, using chemical proteomics approach, we identified ERp57 as a major target of ADTM. ADTM displayed potent inhibitory effects on the redox activity of ERp57, inhibited the adenosine diphosphate (ADP)-induced expressions of P-selectin and αIIbβ3 integrin and disrupted the interaction between ERp57 and αIIbβ3. In addition, ADTM inhibited both arachidonic acid (AA)-induced and ADP-induced platelet aggregationin vitro. Furthermore, ADTM significantly inhibited rat platelet aggregation and thrombus formationin vivo. Taken together, ADTM represents a promising candidate for anti-thrombotic therapy targeting ERp57.