Measurement of Bradykinin Formation and Degradation in Blood Plasma: Relevance for Acquired Angioedema Associated With Angiotensin Converting Enzyme Inhibition and for Hereditary Angioedema Due to Factor XII or Plasminogen Gene Variants.

François Marceau,Arnaud Bonnefoy,Julie M Gauthier,Hannah Laure Elfassy,Karen E Binkley,Isabelle Boccon-Gibod,Hélène Bachelard,Jacques Hébert,Matthieu Picard,Konrad Bork,Laurence Bouillet,Georges E Rivard,Ghislain Levesque

doi:10.3389/fmed.2020.00358

Abstract

Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril maleate in healthy volunteers, finding of possible relevance for the most common form of drug-associated AE. We also addressed the kinetics of immunoreactive BK (iBK) formation and decline, spontaneous or under three standardized stimuli: tissue kallikrein (KLK-1), the particulate material Kontact-APTT™ and tissue plasminogen activator (tPA). Relative to controls, iBK production was rapid (10–20 min) and very intense in response to tPA in plasma of female heterozygotes for variants in gene F12 coding for factor XII (FXII) (p.Thr328Lys, 9 patients; p.Thr328Arg, one). An increased response to Kontact-APTT™ and an early tPA-induced cleavage of anomalous FXII (immunoblots) were also observed. Biotechnological inhibitors showed that the early response to tPA was dependent on plasmin, FXIIa and plasma kallikrein. Results from post-menopausal and pre-menopausal women with HAE-FXII were indistinguishable. The iBK production profiles in seven patients with the plasminogen p.Lys330Glu variant (HAE-PLG) did not significantly differ from those of controls, except for an unexpected, rapid and lanadelumab-resistant potentiation of KLK-1 effect. This enzyme did not cleave plasminogen or factor XII, suggesting a possible idiosyncratic interaction of the plasminogen pathogenic variant with KLK-1 activity. KLK-1 abounds in salivary glands and human saliva, hypothetically correlating with the clinical presentation of HAE-PLG that includes the swelling of the tongue, lips and contiguous throat tissues. Samples from HAE patients with normal C1-INH levels and F12 gene did not produce excessive iBK in response to stimuli. The ex vivo approach provides physiopathological insight into AE states and supports the heterogeneous physiopathology of HAE with normal C1-INH.

Highlights

Bradykinin (BK)-mediated angioedema (AE) is a rare acquired or hereditary condition involving localized edema of the subcutaneous and submucosal tissues
We previously reported that immunoreactive bradykinin (iBK) formation was negligible in either whole blood or plasma incubated at 37◦C without stimulus both in healthy donors and Hereditary angioedema (HAE) patients sampled during remission (HAE-C1-INH type I or II) [20, 21]
The t1/2 increased to 7.1 min when angiotensin-I converting enzyme (ACE) was blocked in vitro with enalaprilat (Figure 2A), suggesting that iBK accumulation is the result of a production rate that surpasses the considerable buffer capacity of peptidases such as ACE

Summary

Introduction

Bradykinin (BK)-mediated angioedema (AE) is a rare acquired or hereditary condition involving localized edema of the subcutaneous and submucosal tissues. Hereditary angioedema (HAE) is a rare autosomal dominant disorder most often caused by variants of the SERPING1 gene encoding C1inhibitor (C1-INH) with impaired production (type I HAEC1-INH) or dysfunctional (type II HAE-C1-INH) forms of this serpin, a polyvalent inhibitor of proteases of the contact system, fibrinolysis and complement. Even rarer forms of HAE with normal C1-INH (HAE-nC1-INH) are caused by mutation of genes encoding coagulation factor XII (F12) [4], plasminogen (PLG) [5], or of kininogens (KNG1) [6], presumably facilitating BK production (Figure 1). A second class of causal genes is suggested by the angiopoietin 1 gene (ANGPT1) mutation associated with a very rare form of HAE-nC1-INH: the structural basis of the endothelial permeability barrier may rather be affected in this case [13]

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Conclusion