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Hereditary Angioedema: a Bradykinin-Mediated Swelling Disorder

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Hereditary Angioedema: a Bradykinin-Mediated Swelling Disorder 368 Theme Issue Article Hereditary angioedema: a bradykinin-mediated swelling disorder Jenny Björkqvist1,2; Anna Sala-Cunill1,3,4; Thomas Renné1,2 1Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden; 2Center of Molecular Medicine, Karolinska Institutet, Stockholm, Sweden; 3Allergy Section, Internal Medicine Department, Hospital Universitari Vall d´Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain; 4Allergy Research Unit, Allergy Department, Institut de Recerca Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain IVBM 2012 Summary be life-threatening involving the skin, the oropharyngeal, laryngeal, Edema is tissue swelling and is a common symptom in a variety of dis- and gastrointestinal mucosa. Three different types of hereditary an- eases. Edema form due to accumulation of fluids, either through re- giodema exist in patients. The review summarises current knowledge duced drainage or increased vascular permeability. There are multiple on the pathophysiology of hereditary angiodema and focuses on re- vascular signalling pathways that regulate vessel permeability. An im- cent experimental and pharmacological findings that have led to a portant mediator that increases vascular leak is the peptide hormone better understanding and new treatments for the disease. bradykinin, which is the principal agent in the swelling disorder hered- itary angioedema. The disease is autosomal dominant inherited and Keywords presents clinically with recurrent episodes of acute swelling that can Contact phase, inflammatory mediators, proteases, SERPINs Correspondence to: Received: August 7, 2012 Thomas Renné, MD, PhD Accepted after major revision: November 8, 2012 Department of Molecular Medicine and Surgery Prepublished online: January 10, 2013 Karolinska Institutet doi:10.1160/TH12-08-0549 Karolinska University Hospital Solna (L1:00) Thromb Haemost 2013; 109: 368–374 SE-171 76 Stockholm, Sweden Tel.: +46 8 517 73390, Fax: +46 310376 E-mail: [email protected] Hereditary angioedema challenging to diagnosis HAE due to variations in the clinical pres- entations. The swellings in HAE patients are highly variable re- Hereditary angiodema (HAE) is a rare inherited disease, which is garding triggering factors, severity, frequency, and localisation. clinically characterised by recurrent acute swelling episodes result- ing from increased vascular permeability. There are about 5,000 affected individuals in Europe. The mechanisms that result in in- Generation of kinins creased vessel leak in HAE are controversial; however, excessive bradykinin (BK) formation due to pathological activation of the Kinins are short-lived hormones that induce many characteristics factor XII (FXII)-driven plasma contact system is a consistent of an inflammatory state, such as changes in blood pressure and finding in acute episodes of HAE. BK belongs to the kinin family vasodilation, pain sensations, leukocyte adhesion, and increased and initiates signalling cascades that increase vascular permeabil- microvascular permeability (5). Kinins form a family of vasoactive ity and induce tissue swelling. Plasma levels of the peptide hor- peptides comprising BK, kallidin (Lys-BK) and their degradation mone are elevated during the swelling attacks (1-5). HAE patients products, respectively. Kinins are produced by two principal path- either carry mutations in the C1 esterase inhibitor (C1INH) pro- ways: the nonapeptide BK is released by limited proteolysis from tein (which is the major inhibitor of the plasma contact system its precursor High-molecular-weight kininogen, (HK) by FXII-ac- proteases, HAE types I and II) or have a mutation in the protease tivated plasma kallikrein (PK) on cell surfaces (7-9). In contrast to factor (F)XII (that is the principal initiator of the plasma contact inducible generation of BK, the decapeptide kallidin is constitut- system, HAE type III). Plasma level of C1INH is reduced in HAE ively produced by tissue kallikrein (TK) predominantly from its type I whereas a dysfunctional protein circulates in type II patient substrate low-molecular-weight kininogen (LK). HK and LK are plasma. Clinical symptoms and swellings are largely similar among splice products of the same gene (10) and accordingly kallidin and the various HAE types. Additionally, there are inherited HAE BK share the identical peptide-sequence with kallidin having one forms that are not linked to known mutations in C1INH or FXII. additional Lysine residue at its N-terminus. In vitro, kallidin can be The identification of the disease-associated defects in these rapidly converted to BK by kinin converting aminopeptidases, families awaits future investigations. Urticaria (itching) is not a which cleave the N-terminal lysine residue (11) (▶ Figure 1). typical feature in HAE patients, indicating that histamine is not of Kininogens and kallikreins are proteins of the plasma contact critical important for the pathology of the disease (6). It is often system that encompasses FXII, and C1-esterase inhibitor (C1INH) Thrombosis and Haemostasis 109.3/2013 © Schattauer 2013 Downloaded from www.thrombosis-online.com on 2013-03-05 | IP: 88.162.114.204 For personal or educational use only. No other uses without permission. All rights reserved. Björkqvist et al. Bradykinin in HAE 369 the major inhibitor of activated PK and FXII (12-14). The plasma Receptors, signalling pathways and contact system is a protease cascade that assembles on cell surface degradation of kinins heparan- and chondroitin-sulfate type proteoglycans (15, 16). Other proteins such as the p33/gC1qR that lacks a transmembrane Kinins are ligands of to two distinct receptor types: kinin B2-re- domain but bears a mitochondrial targeting sequence and is in- ceptor (B2R) and B1-receptor (B1R), respectively, are characte- volved in mitochondrial energy metabolism have been reported to rised by seven transmembrane-spanning helices and are coupled bind HK. Overexpression of heparan sulfates largely increases HK to G proteins in most cells of the Gαq and Gαi families (31, 32). cell binding. In contrast, overexpression of p33/gC1qR does not B1R expression is inducible and is largely up-regulated by cyto- increase HK binding to transfected cells, challenging the in vivo kines such as interleukin-1β (7, 11). Thus, B1R is exposed on cell IVBM 2012 relevance of p33/gC1qR as receptor for HK (15). BK production is surface in response to injury or inflammation. In contrast, B2R is started by FXII coming in contact to surfaces. FXII zymogen bind- constitutively expressed by various cell types, such as endothelial ing to negatively charged surfaces induces a conformational cells, vascular smooth muscle cells and cardiomyocytes (11). Lig- change in the molecule resulting in FXII activation (autoacti- and binding to B1R and B2R initiates signalling cascades that in- vation). Activated FXII (FXIIa) cleaves surface associated plasma crease vascular permeability and fluid efflux in humans (4, 5, 33), prekallikrein to generate PK, which in turn reciprocally activates rats (34), and mice (3). Kinins also activate various other pro-in- further FXII molecules, thereby amplifying the initial signal (17). flammatory signalling pathways such as vessel dilatation, prostag- Plasma prekallikrein and PK are surface-bound via HK. In a com- landin E2 biosynthesis, and induction of chemotaxis of neutro- plex with its substrate HK, PK cleaves the HK peptide bond phils (5, 11, 35). Arg371-Ser372 at the C-terminus of the BK sequence (17). The Kinin-binding to B1R and B2R increases intracellular calcium 2+ 2+ proteolytic step generates a two-chain HK form and BK remains ([Ca ]i) in smooth muscle and endothelial cells. [Ca ]i levels are attached to the C-terminal end of the HK heavy chain (18). A sub- raised through the phospholipase C pathway by inositol 3-phos- sequent second PK-mediated cleavage at Lys362-Arg363 liberates phate (IP3) formation and consecutive InsP3R-mediated Ca2+ re- 2+ BK from the heavy chain (19). Under physiological conditions, lease from intracellular stores. [Ca ]i in turn can activate multiple C1INH controls proteolytic activity of the contact system cascade signalling cascades, including the phospholipase A2 pathway that by inactivating FXIIa and PK-mediated BK generation (14). releases arachidonic acid that is converted to prostacyclines (e.g. C1INH is a member of the serpin protein family, which inhibits PGI2) in a cyclooxygenase-dependent manner. BK also triggers ki- contact system proteases by irreversible binding to their enzymatic nase C (PKC) activity (36) resulting in VASP-mediated disas- pockets (14). In addition to the BK-producing kallikrein-kinin sys- sembly of cortical cytoskeletons (37) and VE-cadherin junctions tem (7, 17) the FXIIa-driven contact system triggers other plasma (38). Similar BK/VASP-dependent pathways may also contribute 2+ protease cascade such as the intrinsic pathway of coagulation, the to angiogenesis (39, 40). Increase in [Ca ]i is a potent stimulator fibrinolytic and the complement systems (17, 20). of endothelial nitric-oxide synthase (eNOS) resulting in NO- Despite having a similar name, TK is nor structurally neither driven protein kinase G activity and VASP phosphorylation (41, evolutionary related to PK (21). TK activations occur intracellul- 42). BK signalling increases Rac1-driven leakage (43). All these arly by evolutionary proteolysis of the serine protease precursor, pathways have a role in BK-driven vasodilation and increased per- tissue prekallikrein.
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