title: Angiotensin 1-9 and 1-7 release in human heart: role of cathepsin A.
abstract: Human heart tissue enzymes cleave angiotensin (Ang) I to release Ang 1-9, Ang II, or Ang 1-7. In atrial homogenate preparations, cathepsin A (deamidase) is responsible for 65% of the liberated Ang 1-9. Ang 1-7 was released (88% to 100%) by a metallopeptidase, as established with peptidase inhibitors. Ang II was liberated to about equal degrees by ACE and chymase-type enzymes. Cathepsin A's presence in heart tissue was also proven because it deamidated enkephalinamide substrate by immunoprecipitation of cathepsin A with antiserum to human recombinant enzyme and by immunohistochemistry. In immunohistochemistry, cathepsin A was detected in myocytes of atrial tissue. The products of Ang I cleavage, Ang 1-9 and Ang 1-7, potentiated the effect of an ACE-resistant bradykinin analog and enhanced kinin effect on the B(2) receptor in Chinese hamster ovary cells transfected to express human ACE and B(2) (CHO/AB), and in human pulmonary arterial endothelial cells. Ang 1-9 and 1-7 augmented arachidonic acid and nitric oxide (NO) release by kinin. Direct assay of NO liberation by bradykinin from endothelial cells was potentiated at 10 nmol/L concentration, 2.4-fold (Ang 1-9) and 2.1-fold (Ang 1-7); in higher concentrations, Ang 1-9 was significantly more active than Ang 1-7. Both peptides had traces of activity in the absence of bradykinin. Ang 1-9 and Ang 1-7 potentiated bradykinin action on the B(2) receptor by raising arachidonic acid and NO release at much lower concentrations than their 50% inhibition concentrations (IC(50)s) with ACE. They probably induce conformational changes in the ACE/B(2) receptor complex via interaction with ACE.
authors.affiliation: Departments of Pharmacology, University of Illinois College of Medicine at Chicago, USA.
authors.forename: Herbert L
authors.initials: HL
authors.lastname: Jackman
authors.forename: Malek G
authors.initials: MG
authors.lastname: Massad
authors.forename: Marin
authors.initials: M
authors.lastname: Sekosan
authors.forename: Fulong
authors.initials: F
authors.lastname: Tan
authors.forename: Viktor
authors.initials: V
authors.lastname: Brovkovych
authors.forename: Branislav M
authors.initials: BM
authors.lastname: Marcic
authors.forename: Ervin G
authors.initials: EG
authors.lastname: Erdös
mesh_terms: D000803:Angiotensin I / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D016466:CHO Cells; D002268:Carboxypeptidases / Q000378:metabolism*; D043402:Cathepsin A; D002478:Cells, Cultured; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D016308:Enkephalin, Leucine-2-Alanine / Q000031:analogs & derivatives* / Q000378:metabolism; D004745:Enkephalins / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D009206:Myocardium / Q000378:metabolism*; D009569:Nitric Oxide / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000378:metabolism
chemical_list: D004745:Enkephalins; D010446:Peptide Fragments; D016718:Arachidonic Acid; D009569:Nitric Oxide; D016308:Enkephalin, Leucine-2-Alanine; C030279:enkephalinamide-Leu, Ala(2)-; D000803:Angiotensin I; D002268:Carboxypeptidases; D010447:Peptide Hydrolases; C468629:CTSA protein, human; D043402:Cathepsin A; D001920:Bradykinin