An antibody against HK blocks Alzheimer's disease peptide β-amyloid-induced bradykinin release in human plasma
An antibody against HK blocks Alzheimer's disease peptide β-amyloid-induced bradykinin release in human plasma
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DOI：
10.1073/pnas.1914831116
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发表时间：
2019-11-12
影响因子：
11.1
通讯作者：
Norris, Erin H.
中科院分区：
文献类型：
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作者：
Chen, Zu-Lin;Singh, Pradeep;Norris, Erin H.
缓激肽是一种促炎因子，在许多疾病中介导血管性水肿和炎症。它是某些类型的遗传性血管性水肿的关键参与者，并参与败血性休克、创伤性损伤、阿尔茨海默病（AD）和中风等。血浆接触系统的激活导致血浆激肽释放酶水平升高，其裂解高分子量激肽原（HK）以释放缓激肽。用于缓激肽介导的病理学的药物开发集中于设计切割HK的酶的抑制剂（以防止缓激肽释放）或内皮缓激肽受体的拮抗剂（以防止下游缓激肽作用）。在这里，我们展示了一种策略，以阻止缓激肽的产生，通过使用HK抗体结合HK，防止其裂解和随后的缓激肽释放。我们表明，这种抗体阻断葡聚糖硫酸钠诱导的HK裂解和缓激肽的生产。此外，虽然致病性AD肽β-淀粉样蛋白（A β）42切割HK并诱导缓激肽产生的急剧增加，但我们的HK抗体阻断了这些事件的发生。这些结果可能为开发缓激肽驱动的病理学治疗提供策略。
Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer's disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent down-stream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide beta-amyloid (A beta)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.