title: Factor XII-independent activation of the bradykinin-forming cascade: Implications for the pathogenesis of hereditary angioedema types I and II.
abstract: BACKGROUND
  We have previously reported that prekallikrein expresses an active site when it is bound to high-molecular-weight kininogen (HK) and can digest HK to produce bradykinin. The reaction is stoichiometric and inhibited by C1 inhibitor (C1-INH) or corn trypsin inhibitor. Addition of heat shock protein 90 leads to conversion of prekallikrein to kallikrein in a zinc-dependent reaction.
  
  
  OBJECTIVE
  Our goal was to determine whether these reactions are demonstrable in plasma and distinguish them from activation through factor XII.
  
  
  METHODS
  Plasma was incubated in polystyrene plates and assayed for kallikrein formation. C1-INH was removed from factor XII-deficient plasma by means of immunoadsorption.
  
  
  RESULTS
  We demonstrate that prekallikrein-HK will activate to kallikrein in phosphate-containing buffers and that the rate is further accelerated on addition of heat shock protein 90. Prolonged incubation of plasma deficient in both factor XII and C1-INH led to conversion of prekallikrein to kallikrein and cleavage of HK, as was seen in plasma from patients with hereditary angioedema but not plasma from healthy subjects.
  
  
  CONCLUSIONS
  These results indicate that C1-INH stabilizes the prekallikrein-HK complex to prevent HK cleavage either by prekallikrein or by prekallikrein-HK autoactivation to generate kallikrein. In patients with hereditary angioedema, kallikrein and bradykinin formation can occur without invoking factor XII activation, although the kallikrein formed can rapidly activate factor XII if it is surface bound.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA. josephk@musc.edu
authors.forename: Kusumam
authors.initials: K
authors.lastname: Joseph
authors.forename: Baby G
authors.initials: BG
authors.lastname: Tholanikunnel
authors.forename: Anette
authors.initials: A
authors.lastname: Bygum
authors.forename: Berhane
authors.initials: B
authors.lastname: Ghebrehiwet
authors.forename: Allen P
authors.initials: AP
authors.lastname: Kaplan
mesh_terms: D054179:Angioedemas, Hereditary / Q000503:physiopathology*; D001920:Bradykinin / Q000378:metabolism*; D003174:Complement C1 Inactivator Proteins / Q000378:metabolism; D050718:Complement C1 Inhibitor Protein; D005174:Factor XII / Q000378:metabolism*; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D056829:Hereditary Angioedema Types I and II / Q000503:physiopathology*; D006801:Humans; D007610:Kallikreins / Q000378:metabolism; D019679:Kininogen, High-Molecular-Weight / Q000378:metabolism*; D008297:Male; D011288:Prekallikrein / Q000378:metabolism*
chemical_list: D003174:Complement C1 Inactivator Proteins; D050718:Complement C1 Inhibitor Protein; D018841:HSP90 Heat-Shock Proteins; D019679:Kininogen, High-Molecular-Weight; C469952:SERPING1 protein, human; D005174:Factor XII; D011288:Prekallikrein; D007610:Kallikreins; D001920:Bradykinin
keywords: (p-Amidinophenyl)methanesulfonyl fluoride; APMSF; Bradykinin; C1 inhibitor; C1-INH; CTI; Corn trypsin inhibitor; HAE; HK; Heat shock protein 90; Hereditary angioedema; High-molecular-weight kininogen; Hsp90; factor XII; kininogen; prekallikrein