The extracellular Ero1α/PDI electron transport system regulates platelet function by increasing glutathione reduction potential.
The extracellular Ero1α/PDI electron transport system regulates platelet function by increasing glutathione reduction potential.
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细胞外 Ero1α/PDI 电子传递系统通过增加谷胱甘肽还原电位来调节血小板功能
DOI：
10.1016/j.redox.2022.102244
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发表时间：
2022-04
期刊：
影响因子：
11.4
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Wang L;Wang X;Lv X;Jin Q;Shang H;Wang CC;Wang L
蛋白质二硫键异构酶（PDI）是一种氧化还原酶，在-Cys-Gly-His-Cys-基序中具有两个相邻的半胱氨酸，它们形成二硫键（S-S）或以巯基形式（-SH）存在，分别形成氧化或还原的PDI。已证明PDI对血小板聚集、血栓形成和止血至关重要，并且PDI抑制被评价为一种新型抗血栓形成策略。然而，在血小板聚集的调节过程中，功能性PDI的氧化还原状态仍有待阐明。内质网氧化还原蛋白1α（Ero 1 α）和PDI是内质网氧化折叠的关键途径，在维持内质网氧化还原平衡中起重要作用。Ero 1 α和PDI是否构成介导血小板聚集的细胞外电子传递途径尚不清楚。在这里，我们发现氧化而不是还原的PDI促进血小板聚集。在血小板表面，Ero 1 α组成型氧化PDI，并以谷胱甘肽依赖性方式进一步调节血小板聚集。Ero 1 α/PDI系统氧化还原型谷胱甘肽（GSH），并建立血小板聚集的最佳还原电位。因此，血小板聚集是由血小板表面的Ero 1 α-PDI-GSH电子传递系统介导的。我们进一步表明，通过小分子抑制剂靶向PDI和Ero 1 α之间的功能性相互作用可能是抗血栓治疗的新策略。氧化而非还原的PDI促进血小板聚集。Ero 1 α和PDI构成血小板表面的电子传递途径。Ero 1 α和PDI为血小板聚集提供了最佳的氧化还原环境。Ero 1 α与PDI的相互作用可能成为抗血小板治疗的新靶点。
Protein disulfide isomerase (PDI), an oxidoreductase, possesses two vicinal cysteines in the -Cys-Gly-His-Cys-motif that either form a disulfide bridge (S–S) or exist in a sulfhydryl form (-SH), forming oxidized or reduced PDI, respectively. PDI has been proven to be critical for platelet aggregation, thrombosis, and hemostasis, and PDI inhibition is being evaluated as a novel antithrombotic strategy. The redox states of functional PDI during the regulation of platelet aggregation, however, remain to be elucidated. Endoplasmic reticulum (ER) oxidoreductin-1α (Ero1α) and PDI constitute the pivotal oxidative folding pathway in the ER and play an important role in ER redox homeostasis. Whether Ero1α and PDI constitute an extracellular electron transport pathway to mediate platelet aggregation is an open question. Here, we found that oxidized but not reduced PDI promotes platelet aggregation. On the platelet surface, Ero1α constitutively oxidizes PDI and further regulates platelet aggregation in a glutathione-dependent manner. The Ero1α/PDI system oxidizes reduced glutathione (GSH) and establishes a reduction potential optimal for platelet aggregation. Therefore, platelet aggregation is mediated by the Ero1α-PDI-GSH electron transport system on the platelet surface. We further showed that targeting the functional interplay between PDI and Ero1α by small molecule inhibitors may be a novel strategy for antithrombotic therapy. Oxidized but not reduced PDI promotes platelet aggregation. Ero1α and PDI constitute an electron transport pathway on platelet surface. Ero1α and PDI provide a redox environment optimal for platelet aggregation. The functional interplay between Ero1α and PDI can be a new target for antiplatelet therapy.
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ERO1Alpha调节二硫化物的低还原电位可确保严格控制底物氧化。
影响因子：
11.4
作者：
Baker, Karl M.;Chakravarthi, Seema;Langton, Kevin P.;Sheppard, Alyson M.;Lu, Hui;Bulleid, Neil J.
通讯作者：
Bulleid, Neil J.
影响因子：
20.1
作者：
Furie B;Flaumenhaft R
通讯作者：
Flaumenhaft R
DOI：
10.1161/atvbaha.114.303410
发表时间：
2015-01
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Flaumenhaft R;Furie B;Zwicker JI
通讯作者：
Zwicker JI
影响因子：
3.9
作者：
LASH, LH;JONES, DP
通讯作者：
JONES, DP
影响因子：
20.3
作者：
Kim, Kyungho;Hahm, Eunsil;Cho, Jaehyung
通讯作者：
Cho, Jaehyung