| Autor: |
de Maat, Steven, Sanrattana, Wariya, Mailer, Reiner K., Parr, Naomi M. J., Hessing, Martin, Koetsier, Robert M., Meijers, Joost C. M., Pasterkamp, Gerard, Renné, Thomas, Maas, Coen |
| Zdroj: |
Blood; November 2019, Vol. 134 Issue: 19 p1658-1669, 12p |
| Abstrakt: |
The contact system produces the inflammatory peptide bradykinin and contributes to experimental thrombosis. C1 esterase-inhibitor (C1INH) deficiency or gain-of-function mutations in factor XII (FXII) cause hereditary angioedema, a life-threatening tissue swelling disease. C1INH is a relatively weak contact system enzyme inhibitor. Although a1-antitrypsin (a1AT) does not naturally inhibit contact system enzymes, a human mutation (M358R; a1AT-Pittsburgh) changes it into a powerful broad-spectrum enzyme inhibitor. It blocks the contact system, but also thrombin and activated protein C (APC), making it an unattractive candidate for therapeutic contact system blockade. We adapted the reactive center loop of a1AT-Pittsburgh (AIPR/S) to overcome these obstacles. Two a1AT variants (SMTR/S and SLLR/S) strongly inhibit plasma kallikrein, activated FXII, and plasmin. a1AT-SMTR/S no longer inhibits thrombin, but residually inhibits APC. In contrast, a1AT-SLLR/S residually inhibits thrombin, but no longer APC. Additional modification at the P1' position (S?V) eliminates residual inhibition of thrombin and APC for both variants, while retaining their properties as contact system inhibitors. Both a1AT-SMTR/V and -SLLR/V are superior to C1INH in reducing bradykinin production in plasma. Owing to their capacity to selectively block contact system-driven coagulation, both variants block vascular occlusion in an in vivo model for arterial thrombosis. Furthermore, both variants block acute carrageenan-induced tissue edema in mice. Finally, a1AT-SLLR/V, our most powerful candidate, suppresses epithelial leakage of the gut in a mouse model of colitis. Our findings confirm that redesign of a1AT strongly alters its inhibitory behavior and can be used for the treatment of contact system-mediated thrombosis and inflammation. |
| Databáze: |
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