Both plasma basic carboxypeptidases, carboxypeptidase B2 and carboxypeptidase N, regulate vascular leakage activity in mice.

Autor: Zhou Q; Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA., Zhao L; Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA., Shao Z; Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA., Declerck P; Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, Belgium., Leung LLK; Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA., Morser J; Division of Hematology, Stanford University School of Medicine, Stanford, California, USA.; Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Jazyk: angličtina
Zdroj: Journal of thrombosis and haemostasis : JTH [J Thromb Haemost] 2022 Jan; Vol. 20 (1), pp. 238-244. Date of Electronic Publication: 2021 Nov 07.
DOI: 10.1111/jth.15551
Abstrakt: Background: Kallikrein is generated when the contact system is activated, subsequently cleaving high molecular weight kininogen to bradykinin (BK). BK binds to bradykinin receptor 2, causing vascular leakage. BK is inactivated by proteolysis by the plasma carboxypeptidase B2 and N (CPB2 and CPN). CPN is constitutively active but CPB2 is generated from its zymogen, proCPB2.
Objectives: Determine the role of CPB2 and CPN in the regulation of vascular leakage.
Methods: Mice deficient in CPB2, CPN, or both (Cpb2 -/- , Cpn -/- , and Cpb2 -/- /Cpn -/- ) were compared with wild-type mice (WT) in a model of vascular leakage caused by skin irritation. In some experiments, mice were pretreated with antibodies that prevent activation of proCPB2.
Results: Skin irritation increased vascular leakage most in Cpb2 -/- /Cpn -/- , less in Cpb2 -/- and Cpn -/- , and least in WT mice. There was no difference in vascular leakage without the challenge. Antibodies inhibiting activation of proCPB2 by plasmin, but not by the thrombin/thrombomodulin complex, increased vascular leakage to the level seen in Cpb2 -/- mice. There was no change in levels of markers of coagulation and fibrinolysis.
Conclusions: Bradykinin is inactivated by both CPB2 and CPN independently. Plasmin is the activator of proCPB2 in this model. Mice lacking both plasma carboxypeptidases have more vascular leak than those lacking either alone. Although BK levels were not determined, BK is the likely substrate for CPB2 and CPN in this model.
(© 2021 International Society on Thrombosis and Haemostasis.)
Databáze: MEDLINE
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