JCI：芦丁阻止血栓形成的分子机制

芦丁，是一种黄酮类化合物，常见于果实和蔬菜中，也可作为膳食被充剂在柜台出售，能抑制血栓模型动物的血栓形成。最新发表在期刊The Journal of Clinical Investigation (JCI)上的研究指出黄酮类化合物可预防和治疗中风、心脏病发作、深静脉血栓（DVT）和肺栓塞，为预防血栓形成提供了一种新策略，同时，为黄酮疗法的临床测试铺平了一条道路。

该研究重点观察了蛋白质二硫键异构酶（PDI），此酶存在于所有细胞中，在血栓形成期间可迅速从血小板和内皮细胞分泌，是预防血栓形成的潜在靶标。若血块在血管中形成，此时PDI的抑制就能阻止模型小鼠的血栓形成。

因为细胞内PDI是蛋白适当合成所必需的，所以必须鉴定出一种特异性化合物，要求它能阻止引发血栓形成的细胞外PDI，但不抑制细胞内PDI。因而，研究人员对大量化合物进行高通量筛选，以便找到PDI抑制剂。在筛查的5000多种化合物中，芦丁（又名槲皮黄酮-3-芸香甙）脱颖而出，它分子中的同一部分既有抑制PDI的能力，又能抑制化合物进入细胞内。研究证实，芦丁是一种抗血栓化合物，对血栓形成期间的血小板累积与纤维蛋白产生都有抑制作用，能治疗与预防两种类型血栓，即血小板富集型与纤维蛋白富集型。

doi:10.1172/JCI61228
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Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Reema Jasuja, Freda H. Passam, Daniel R. Kennedy, Sarah H. Kim, Lotte van Hessem, Lin Lin, Sheryl R. Bowley, Sucharit S. Joshi, James R. Dilks, Bruce Furie, Barbara C. Furie, Robert Flaumenhaft

Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.