Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.
Department of Chemistry, University of Georgia, Athens, GA.
Blood. 2022 May 5;139(18):2816-2829. doi: 10.1182/blood.2021012945.
Patients with hereditary angioedema (HAE) experience episodes of bradykinin (BK)-induced swelling of skin and mucosal membranes. The most common cause is reduced plasma activity of C1 inhibitor, the main regulator of the proteases plasma kallikrein (PKa) and factor XIIa (FXIIa). Recently, patients with HAE were described with a Lys311 to glutamic acid substitution in plasminogen (Plg), the zymogen of the protease plasmin (Plm). Adding tissue plasminogen activator to plasma containing Plg-Glu311 vs plasma containing wild-type Plg (Plg-Lys311) results in greater BK generation. Similar results were obtained in plasma lacking prekallikrein or FXII (the zymogens of PKa and FXIIa) and in normal plasma treated with a PKa inhibitor, indicating Plg-Glu311 induces BK generation independently of PKa and FXIIa. Plm-Glu311 cleaves high and low molecular weight kininogens (HK and LK, respectively), releasing BK more efficiently than Plm-Lys311. Based on the plasma concentrations of HK and LK, the latter may be the source of most of the BK generated by Plm-Glu311. The lysine analog ε-aminocaproic acid blocks Plm-catalyzed BK generation. The Glu311 substitution introduces a lysine-binding site into the Plg kringle 3 domain, perhaps altering binding to kininogens. Plg residue 311 is glutamic acid in most mammals. Glu311 in patients with HAE, therefore, represents reversion to the ancestral condition. Substantial BK generation occurs during Plm-Glu311 cleavage of human HK, but not mouse HK. Furthermore, mouse Plm, which has Glu311, did not liberate BK from human kininogens more rapidly than human Plg-Lys311. This indicates Glu311 is pathogenic in the context of human Plm when human kininogens are the substrates.
遗传性血管性水肿（HAE）患者会出现缓激肽（BK）诱导的皮肤和黏膜肿胀发作。最常见的原因是血浆激肽释放酶抑制剂（C1 抑制剂）活性降低，C1 抑制剂是血浆激肽原酶（PKa）和因子 XIIa（FXIIa）的主要调节剂。最近，有研究描述了一种纤溶酶原（Plg）中的赖氨酸 311 突变为谷氨酸（Plg-Glu311）的 HAE 患者，Plg 是蛋白酶纤溶酶（Plm）的酶原。将组织型纤溶酶原激活物加入含有 Plg-Glu311 的血浆与含有野生型 Plg（Plg-Lys311）的血浆相比，会导致更多的 BK 生成。在缺乏前激肽释放酶或 FXII（PKa 和 FXIIa 的酶原）的血浆以及用 PKa 抑制剂处理的正常血浆中也得到了类似的结果，表明 Plg-Glu311 诱导 BK 生成独立于 PKa 和 FXIIa。Plm-Glu311 可裂解高分子量和低分子量激肽原（HK 和 LK），比 Plm-Lys311 更有效地释放 BK。根据 HK 和 LK 的血浆浓度，后者可能是 Plm-Glu311 生成的大部分 BK 的来源。赖氨酸类似物 ε-氨基己酸可阻断 Plm 催化的 BK 生成。Glu311 取代将赖氨酸结合位点引入 Plg 克拉夫特 3 结构域，可能改变与激肽原的结合。在大多数哺乳动物中，Plg 残基 311 为谷氨酸。因此，HAE 患者中的 Glu311 代表了向祖先条件的回归。Plm-Glu311 切割人 HK 时会产生大量 BK，但不会切割鼠 HK。此外，具有 Glu311 的鼠 Plm 从人激肽原释放 BK 的速度并不快于人 Plg-Lys311。这表明当人激肽原作为底物时，Glu311 在人 Plm 中是致病的。
